tag:blogger.com,1999:blog-69712933767256429982024-03-14T05:45:38.763-07:00Drug Discovery with Quantum PharmaceuticalsPeter Fedichev (Quantum CTO)http://www.blogger.com/profile/06881436001010579010noreply@blogger.comBlogger49125tag:blogger.com,1999:blog-6971293376725642998.post-72086958247758616622009-12-02T22:45:00.000-08:002009-12-02T22:47:06.212-08:00The Blog has movedto another location. The blog feed is now merged with the Quantum Pharmaceuticals official site <a href="http://www.q-pharm.com">http://q-pharm.com</a>. See you there!Peter Fedichev (Quantum CTO)http://www.blogger.com/profile/06881436001010579010noreply@blogger.com192tag:blogger.com,1999:blog-6971293376725642998.post-9930535889396194212009-08-31T01:14:00.000-07:002009-09-14T08:38:13.863-07:00The nature of phospholipid membranes repulsion at nm-distancesWhy hydrophobic membranes repel at small distances? We apply recently developed phenomenological theory of polar liquids to calculate the repulsive pressure between two hydrophilic membranes at nm-distances. We find that the repulsion does show up in the model and the solution to the problem fits the published experimental data well both qualitatively and quantitatively. Moreover, we find that the repulsion is practically independent on temperature, and thus put some extra weight in favor of the so called hydration over entropic hypothesis for the membranes interactions explanation. The calculation is a good “proof of concept” example a continuous water model application to non-trivial interactions on nm-size bodies in water arising from long-range correlations between the water molecules.<br /><a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgwDPfY7BnCGZVwIZdh_gg6bt1qq_6PgjGjIMzL0P_FJ1xOsAZtVvJFByeTPUDslU2M9-F15C6fBlOxySG2h8v0BvxI4EwMzoIMWTf4EO13i_BQaISOJzAfFpsUgVFi1eoBU32XPOSI4I7w/s1600-h/Polarization+of+water+between+membranes.png"><img style="margin: 0px auto 10px; display: block; text-align: center; cursor: pointer; width: 320px; height: 224px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgwDPfY7BnCGZVwIZdh_gg6bt1qq_6PgjGjIMzL0P_FJ1xOsAZtVvJFByeTPUDslU2M9-F15C6fBlOxySG2h8v0BvxI4EwMzoIMWTf4EO13i_BQaISOJzAfFpsUgVFi1eoBU32XPOSI4I7w/s320/Polarization+of+water+between+membranes.png" alt="" id="BLOGGER_PHOTO_ID_5376039465618314738" border="0" /></a>More details can be found here:<br /><br /> <span class="list-identifier"><a href="http://xxx.lanl.gov/abs/0908.0632" title="Abstract">arXiv:0908.0632</a> [<a href="http://xxx.lanl.gov/pdf/0908.0632" title="Download PDF">pdf</a>, <a href="http://xxx.lanl.gov/format/0908.0632" title="Other formats">other</a>] </span><div class="list-title"><span class="descriptor"></span>The nature of phospholipid membranes repulsion at nm-distances </div> <div class="list-authors"> <span class="descriptor">Authors:</span> <a href="http://xxx.lanl.gov/find/cond-mat/1/au:+Fedichev_P/0/1/0/all/0/1">P. O. Fedichev</a>, <a href="http://xxx.lanl.gov/find/cond-mat/1/au:+Menshikov_L/0/1/0/all/0/1">L.I. Menshikov</a> </div>Peter Fedichev (Quantum CTO)http://www.blogger.com/profile/06881436001010579010noreply@blogger.com1tag:blogger.com,1999:blog-6971293376725642998.post-57260533821985645352009-06-20T01:18:00.000-07:002009-06-20T01:23:02.786-07:00hERG binding correlates with LogP?Here is a very good analysis from <a href="http://homepage.mac.com/swain/Sites/CMC/DDResources/herg_activity.html">human ERG blockers article</a>:<br /><br />The plot below (created using<a target="_blank" href="http://homepage.mac.com/swain/Macinchem/Reviews/Vortex_review/vortex.html" rel="external">Vortex</a>)shows pIC50 calculated from the literature IC50 data versus calculated logP determined using<a target="_blank" href="http://www.vcclab.org/lab/alogps/" rel="external">alogPS</a>, the colour coding shows the overall general tend of increasing hERG activity as logP increases, it also highlights the reduced liability seen with acids (green) and zwitterions (red).<br /> <br /> <img class="imageStyle" alt="ikr_bnd_data" src="http://homepage.mac.com/swain/Sites/CMC/DDResources/herg_activity_files/ikr_bnd_data.png" width="673" height="726" /> <br /> <br /> Whilst the majority of data is derived from radioligand binding experiments (using either Dofetilide or MK-499), there is a substantial amount of data from patch clamp experiments, I collated enough data now (covering 4 orders of magnitude) to give an idea of how the assays compare. As you can see there is a reasonable correlation between the assays, but there are one or two outliers. Which is more predictive of in vivo activity is an excellent question that I don’t have the data to answer yet. <br /> <br /><img class="imageStyle" alt="patc_v_bnd" src="http://homepage.mac.com/swain/Sites/CMC/DDResources/herg_activity_files/patc_v_bnd.png" width="679" height="720" /><br /><br /> I still need to increase the size of the data-set, and if anyone can direct me to any publicly available data, or to publications that contain data i'd much appreciate it.<br /> Worth reading, Medicinal Chemistry of hERG Optimizations: Highlights and Hang-Ups, Jamieson, Journal of Medicinal Chemistry, 2006, 5029Peter Fedichev (Quantum CTO)http://www.blogger.com/profile/06881436001010579010noreply@blogger.com2tag:blogger.com,1999:blog-6971293376725642998.post-21405095310088179212009-04-06T11:45:00.001-07:002009-04-06T12:04:01.065-07:00Molecular polarization on a polar liquid interface: the structure of a water surface<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjcUXgyXarULGAfssdYKesS6YQzuWERU8YU5ULmGNwu3ajrYPbWWKYkJeU8211omF7zv5TzpJNCCLBbeolJPlGsE8bTxXPLf_RjilqZHjTyrOup6wCMIrrlAMFsk63qNzswHBoWvKZVTjnk/s1600-h/density.png"><img style="margin: 0pt 10px 10px 0pt; float: left; cursor: pointer; width: 320px; height: 186px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjcUXgyXarULGAfssdYKesS6YQzuWERU8YU5ULmGNwu3ajrYPbWWKYkJeU8211omF7zv5TzpJNCCLBbeolJPlGsE8bTxXPLf_RjilqZHjTyrOup6wCMIrrlAMFsk63qNzswHBoWvKZVTjnk/s320/density.png" alt="" id="BLOGGER_PHOTO_ID_5321653420900649202" border="0" /></a>The orientations of water molecules within the liquid depend on interplay of long-range dipole-dipole interaction and short range hydrogen-bonding interactions. At room temperature water is in paraelectric (disordered) phase and thus average dipole moment of any large enough fraction of the liquid vanishes.<br /><br />This observation is not necessarily true at the liquid boundary. Since no molecules "like" to point at a hydrophobic interface direction (this would imply many uncompensated hydrogen bonds), most of the molecules orient along the liquid surface, the boundary between the liquid and a hydrophobic may become polarized (become essentially ferroelectric). Practically this amounts to a formation of stable network of hydrogen bonds on the interface.<br /><br /><a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgMAVNkj8DC58DYOATXdFWulwRpVRQj8ckwx0i9adz9MZ4OMs47jBBvzP5V6fszJh3-LPIZsK4IMG2ixv7VNbn2mGLiYCQaF4UcPWX2t-KccMm1BM1q6QWqiEvWlAYydbahs3tMScm4_Isw/s1600-h/polarization.png"><img style="margin: 0pt 10px 10px 0pt; float: left; cursor: pointer; width: 320px; height: 214px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgMAVNkj8DC58DYOATXdFWulwRpVRQj8ckwx0i9adz9MZ4OMs47jBBvzP5V6fszJh3-LPIZsK4IMG2ixv7VNbn2mGLiYCQaF4UcPWX2t-KccMm1BM1q6QWqiEvWlAYydbahs3tMScm4_Isw/s320/polarization.png" alt="" id="BLOGGER_PHOTO_ID_5321654280839022034" border="0" /></a> The solution corresponding to such polarized boundary can be obtained in the very latest "incarnation" of the QUANTUM water model (See the attached figures). The first one demonstrates the density of the liquid starting from the gas phase on the left (model liquid density 0.3) and to the liquid phase (model density 1). The transition between the two phases is similar to that in classical model of van der Waals liquid.<br /><br />The second graph corresponds to the polarization density (mean dipole moment of a liquid volume). Comparing the two graphs we see that the interface is indeed polarized and the polarization decays quickly into the bulk both of the gas and the liquid phase and, as the detailed calculation shows, contributes to the surface tension coefficient considerably.<br /><br />In short we observe that depending on the ordering state of the water layer next to a molecular surface the effective surface tension may be different by a large number. Another observation suggests that the water density depletion next to a fully hydrophobic (and thus ordering) surface can be large (up to 30-50%)Peter Fedichev (Quantum CTO)http://www.blogger.com/profile/06881436001010579010noreply@blogger.com4tag:blogger.com,1999:blog-6971293376725642998.post-63527287270761555212009-03-11T02:24:00.000-07:002009-09-14T08:41:30.475-07:00New Quantum Water Model helps find stable ss DNA conformation in solution<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="http://upload.wikimedia.org/wikipedia/commons/thumb/9/9e/Parallel_telomere_quadruple.png/300px-Parallel_telomere_quadruple.png"><img style="margin: 0pt 0pt 10px 10px; float: right; cursor: pointer; width: 300px; height: 274px;" src="http://upload.wikimedia.org/wikipedia/commons/thumb/9/9e/Parallel_telomere_quadruple.png/300px-Parallel_telomere_quadruple.png" alt="" border="0" /></a><br /><center><iframe allowfullscreen='allowfullscreen' webkitallowfullscreen='webkitallowfullscreen' mozallowfullscreen='mozallowfullscreen' width='320' height='266' src='https://www.blogger.com/video.g?token=AD6v5dwCearZrV5MIB_JB9XI6F3KRvV0Trk59IKYQF1FeX1-07WVYdhyDgFuoSslXTnX2ikS9ajiNanRPtob3I59Ww' class='b-hbp-video b-uploaded' frameborder='0'></iframe></center><br />ss DNA Molecular dynamics trajectory using the latest Quantum force field helps to find a perfectly stable conformation of the biomolecule in solution. The outcome of the simulation is very reasonable, given the fact that ss DNA (such as telomers) tend indeed to form such loops (see the Figure on the right). The Figure shows the structure of a DNA quadruplex formed by telomere repeats. The conformation of the DNA backbone diverges significantly from the typical helical structurePeter Fedichev (Quantum CTO)http://www.blogger.com/profile/06881436001010579010noreply@blogger.comtag:blogger.com,1999:blog-6971293376725642998.post-20233422499012451842009-01-23T12:16:00.000-08:002009-01-23T23:11:44.911-08:00Solvation energy of a large atom cluster: continuous solvation energy test - II<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgqguGjpHPB3k-ExqvbjBcdqAFWal5OyFNayDqA8M6enGe5QSGDcHwGO6ig9xFEsmvz0G9Iw9Qe-srqZb4JhapER7HtG0w_h2InBzNsTJN5eDYVlc9oBa4t8gSkAupzMHNDSJbrVJrnQZas/s1600-h/atom_exiting_sphere_A.png"><img style="margin: 0pt 10px 10px 0pt; float: left; cursor: pointer; width: 277px; height: 320px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgqguGjpHPB3k-ExqvbjBcdqAFWal5OyFNayDqA8M6enGe5QSGDcHwGO6ig9xFEsmvz0G9Iw9Qe-srqZb4JhapER7HtG0w_h2InBzNsTJN5eDYVlc9oBa4t8gSkAupzMHNDSJbrVJrnQZas/s320/atom_exiting_sphere_A.png" alt="" id="BLOGGER_PHOTO_ID_5294586232187946514" border="0" /></a>As it has been already stated here, binding energy calculation of a small molecule to a large protein poses a difficult problem: a method for molecular electrostatic energy calculation should work well both for the protein ligand complex, the protein and the ligand at infinite separation. The protein and the complex are large molecules, whereas the ligand is, by definition, small.<br /><br />Not every computational approach for the solvation energy calculation is fit for the job though. To elucidate the nature of the problems at hand we performed the following model calculation:<br />- we prepared a spherical "protein" of a large (but realistic) radius<br />- we placed a single-atom ligand with a charge at a given distance from the "protein" center (see the Figure)<br />- we calculated the solvation energy of the system as a function of the ligand distance both when the protein is neutral and charged (in the latter case the protein charge is opposite to that of the "ligand")<br /><a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhThAd7slYfFOG08MlybhC9tZmaHj37fBsK_-AjjX7UUwNtOBhvCigNOe0Bl84DOs5XtqwU0rzuqOpt7uo7ER4WMYtEZvZ7o0SsZ-GF8zziAtSvIaGJ2PztUIFIEEQVqip1A4OVcT0AOEba/s1600-h/clustercharge0.png"><img style="margin: 0pt 0pt 10px 10px; float: right; cursor: pointer; width: 320px; height: 242px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhThAd7slYfFOG08MlybhC9tZmaHj37fBsK_-AjjX7UUwNtOBhvCigNOe0Bl84DOs5XtqwU0rzuqOpt7uo7ER4WMYtEZvZ7o0SsZ-GF8zziAtSvIaGJ2PztUIFIEEQVqip1A4OVcT0AOEba/s320/clustercharge0.png" alt="" id="BLOGGER_PHOTO_ID_5294588441480869746" border="0" /></a><br />We used four different methods for the electrostatic contribution to the solvation energy calculation: Poisson equation solver (in its surface electrostatic incarnation, blue) QUANTUM MGB (cyan) and the two "classic" GB methods, based on the Coulomb approximation: HCT (magenta) and AGBNP (yellow).<br /><br />The first Figure, corresponding to an overall electrically neutral cluster, shows absolute deficiency of HCT approach deep enough inside the "protein". The problem is caused by unrealistic assumptions with regard to the overlap integrals calculations is occurs pretty frequently in realistic proteins. AGBNP method represents one of the latest GB approaches and is practically free of these difficulties. However, AGBNP is based on Coulomb approximation and thus fails to recover correct behavior of the solvation energy close to the "protein" boundary: AGBNP energy is off by a large number from both QMGB and the exact solution. QMGB and Poisson solutions agree very well everywhere!<br /><a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjBOJW02mfDEsz9rcd3POlGmrlz7_EOWM989ZkrCS8sioqCFkFunXEXOiuY6QXjPhZcHFOK0RicLF18z9VJ8wnj__6S69MiWQ6t7nLAjxxmHR4miyxbPQE1baIIfdg1CRbkTWutWAd9oxS_/s1600-h/clustercharge1.png"><img style="margin: 0pt 0pt 10px 10px; float: right; cursor: pointer; width: 320px; height: 226px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjBOJW02mfDEsz9rcd3POlGmrlz7_EOWM989ZkrCS8sioqCFkFunXEXOiuY6QXjPhZcHFOK0RicLF18z9VJ8wnj__6S69MiWQ6t7nLAjxxmHR4miyxbPQE1baIIfdg1CRbkTWutWAd9oxS_/s320/clustercharge1.png" alt="" id="BLOGGER_PHOTO_ID_5294590543677258418" border="0" /></a><br />The last Figure shows the same calculation for a charged model "protein-ligand" complex. Once again, HCT fails entirely, AGBNP does not work properly at the "protein" boundary and both Poisson solver and QMGB agree very well, though QMGB is about one order of magnitude faster than the Poisson solver!<br /><br />Practically all this means that QMGB represents a fast and accurate approximation to the Poisson equation solution. QMGB approach does not rely on Coulomb approximation and is shown to work both for <a href="http://drugdiscoverywizzards.blogspot.com/2009/01/solvation-energy-of-diatomic-molecule.html">small molecules</a> and large molecular clusters involving molecules of very different sizes. Therefore, with QMGB one can find a single <a href="http://drugdiscoverywizzards.blogspot.com/2009/01/self-consistent-solvation-energy.html">transferable</a> set of GB parameters capable of describing large and small molecules on the same footing.Peter Fedichev (Quantum CTO)http://www.blogger.com/profile/06881436001010579010noreply@blogger.com0tag:blogger.com,1999:blog-6971293376725642998.post-59059912641355739912009-01-23T01:06:00.000-08:002009-01-23T11:59:09.272-08:00Solvation energy of a diatomic molecule: continuous solvation energy test - I<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjyOBxV7U0MbJETYy7UVY_0tFvZwLUyD05UEUqzDVu_Xl_HTvOhhnYbYtiuhXRlxph4xoh5uI963rSHCe57g1kgdn9nfIpUufnhs9JbKIgY38_Z0Uv-gVfwB4VAM_cIdDU84wZzEQbIOl9n/s1600-h/atom_pair.png"><img style="margin: 0pt 10px 10px 0pt; float: left; cursor: pointer; width: 320px; height: 280px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjyOBxV7U0MbJETYy7UVY_0tFvZwLUyD05UEUqzDVu_Xl_HTvOhhnYbYtiuhXRlxph4xoh5uI963rSHCe57g1kgdn9nfIpUufnhs9JbKIgY38_Z0Uv-gVfwB4VAM_cIdDU84wZzEQbIOl9n/s320/atom_pair.png" alt="" id="BLOGGER_PHOTO_ID_5294415102029494594" border="0" /></a> Diatomic molecule is the simplest example of a realistic solvation energy calculation. Indeed, any reasonable solvation energy model gives exact value for a single atom.<br /><br />Depending on the radii of the atoms involved the solvation energy of a pair may be a very good test of a solvation energy model and <a href="http://drugdiscoverywizzards.blogspot.com/2009/01/self-consistent-solvation-energy.html">transferability of its parameters</a>. In what follows we show the results of our Modified GB (MGB) approach for the test system. The graph below represents the solvation energies for similar and opposite charges pairs.<br /><br />The upper (blue) solid curve represents the atom pair with opposite charges, whereas the lower (red) curve corresponds to the atoms with similar charges. First of all, the behavior of the two energies is easy to understand. At infinite separation both curves saturate at <span style="font-style: italic;">-0.125</span> (which is the Born solvation energy of the two charges of <span style="font-style: italic;">0.5</span> and bare radii <span style="font-style: italic;">2.</span>). If the total charge is <span style="font-style: italic;">0</span> (the opposite charges case, blue curve), at <span style="font-style: italic;">r=0</span> we have <span style="font-style: italic;">Es=0</span> as well. If the total charge is <span style="font-style: italic;">2x0.5=1</span> (the red curve), then at <span style="font-style: italic;">r=0</span> we have <span style="font-style: italic;">Es=-0.25</span>, as it should be for a combined charge within the sphere of radius <span style="font-style: italic;">2</span>.<br /><br /><a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjRvmTl-DH0HqW81gq1vimtGlxhw5HS998QTnlF_5hlsPTj8jdo2QCFtgPZNUA2UsuIfgU9D05qC8hS9X9ftDKfhV-q12X4eO_WPGQLrg8MLAoG3baE3FkJMSP2Iln0qm7LAIWTHDZNKXgB/s1600-h/pair_energy.png"><img style="margin: 0pt 10px 10px 0pt; float: left; cursor: pointer; width: 296px; height: 230px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjRvmTl-DH0HqW81gq1vimtGlxhw5HS998QTnlF_5hlsPTj8jdo2QCFtgPZNUA2UsuIfgU9D05qC8hS9X9ftDKfhV-q12X4eO_WPGQLrg8MLAoG3baE3FkJMSP2Iln0qm7LAIWTHDZNKXgB/s320/pair_energy.png" alt="" id="BLOGGER_PHOTO_ID_5294417788937398642" border="0" /></a>Although the asymptotic values are OK, this does not mean the whole curve is fine. To compare our approach with true electrostatic we performed the calculation of the model system solving the Poisson equation as well as by two "classic" GB models (that of HCT and AGNP). The results for a diatomic molecule with zero total charge are represented on the last graph.<br /><a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiCXW_zmfyakqb14oByZ1x4NMFK5gCiwt4RPVnJAU6Hksav4RzXiyrE4Mu0arhFjHT_Q7cpEumiEauzo51LV26f77Y91JjdA3JzKLtFDNDJZn1cn2JYFem6j4TBYrrwEBDme8ahV7At0ZDS/s1600-h/diatomcharge0.png"><img style="margin: 0pt 0pt 10px 10px; float: right; cursor: pointer; width: 320px; height: 226px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiCXW_zmfyakqb14oByZ1x4NMFK5gCiwt4RPVnJAU6Hksav4RzXiyrE4Mu0arhFjHT_Q7cpEumiEauzo51LV26f77Y91JjdA3JzKLtFDNDJZn1cn2JYFem6j4TBYrrwEBDme8ahV7At0ZDS/s320/diatomcharge0.png" alt="" id="BLOGGER_PHOTO_ID_5294576011726966674" border="0" /></a><br />The electrostatic part of the solvation energy corresponds to the blue curve of the previous graph and is calculated either by a (surface-electrostatic) Poisson equation solver (blue), QUANTUM's MGB (cyan), AGBNP (yellow) and HCT GB model (yellow). As it is clear from here, all the approaches give very similar results for the "small" molecule and are practically indistinguishable. Indeed, it is well known that practically any sort of GB approximation gives good results for solvation energies of small molecules.<br /><a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiZ7fmPYbdPW33FhXSAGLgFmq8tC6ZKiZeZ-jvNefT6F3-iJQEaMpD-gFYEC-eRqqN1ODb7e2Tk04gUfeR2GVCsfQuU-dORViAVcN0yMk96BwI7l-_Nphs_zbxvEEYYx-a0ekHgAXEnjkFM/s1600-h/diatomcharge1.png"><img style="margin: 0pt 0pt 10px 10px; float: right; cursor: pointer; width: 320px; height: 237px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiZ7fmPYbdPW33FhXSAGLgFmq8tC6ZKiZeZ-jvNefT6F3-iJQEaMpD-gFYEC-eRqqN1ODb7e2Tk04gUfeR2GVCsfQuU-dORViAVcN0yMk96BwI7l-_Nphs_zbxvEEYYx-a0ekHgAXEnjkFM/s320/diatomcharge1.png" alt="" id="BLOGGER_PHOTO_ID_5294579973891910514" border="0" /></a><br />The difference between QMGB method and "classic" GB approaches and its relation to the exact solution becomes more obvious if we consider a charged diatomic molecule (a molecular ion with total charge, say, <span style="font-style: italic;">1</span> placed on one of the atoms). The exact (blue) and QMGB (cyan), once again, are both in agreement with each other, whereas both "classic" GB approaches, HCT and AGBNP fail to recover correct asymptotic value at zero inter-atomic separation. The latter difference between GB solutions and the exact value of the solvation energy is not important for small molecules (low atom density) but is extremely important for ligand binding calculations (to be explained).Peter Fedichev (Quantum CTO)http://www.blogger.com/profile/06881436001010579010noreply@blogger.com40tag:blogger.com,1999:blog-6971293376725642998.post-17589431920896989312009-01-13T03:20:00.000-08:002009-01-23T01:19:04.483-08:00Self-consistent solvation energy contribution calculation for protein-ligand complexes<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgQUDnomcOQT5vNal1ouOzlgBHdEEMRX_nSEIsw_tNTtDinRDa1297XSbt-2LBis82AiU9LQ0Nm9bczYdi8Vts1b5j01N7VRLPpbhHsfEypC11BuU98YUD_WYL9BxesoGCrzu9iFQ9GIPrH/s1600-h/correlationEbind2009.png"><img style="margin: 0pt 0pt 10px 10px; float: right; cursor: pointer; width: 320px; height: 262px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgQUDnomcOQT5vNal1ouOzlgBHdEEMRX_nSEIsw_tNTtDinRDa1297XSbt-2LBis82AiU9LQ0Nm9bczYdi8Vts1b5j01N7VRLPpbhHsfEypC11BuU98YUD_WYL9BxesoGCrzu9iFQ9GIPrH/s320/correlationEbind2009.png" alt="" id="BLOGGER_PHOTO_ID_5290737887606151250" border="0" /></a><br /><a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhLS2YR81ny0SYZkWNPZ9L_UclD-1MNQ2Oz-S7gj-K2NP7HqqjnQKv1cOjnHV50vsaw1_6lvWxH1sbRCjLGi5oibXvcBWhb0tGDAYtf5xlgf7O6uI2j2GoTHsUoohvjSkAmp7auk1yl-vZq/s1600-h/CorrEsolv2009.png"><img style="margin: 0pt 10px 10px 0pt; float: left; cursor: pointer; width: 320px; height: 230px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhLS2YR81ny0SYZkWNPZ9L_UclD-1MNQ2Oz-S7gj-K2NP7HqqjnQKv1cOjnHV50vsaw1_6lvWxH1sbRCjLGi5oibXvcBWhb0tGDAYtf5xlgf7O6uI2j2GoTHsUoohvjSkAmp7auk1yl-vZq/s320/CorrEsolv2009.png" alt="" id="BLOGGER_PHOTO_ID_5290737431999197202" border="0" /></a><br /><br />Solvation energy is a major contribution to a ligand binding energy and is the interaction pretty much responsible for binding selectivity. Actual calculation of the solvation energy requires a method valid both for small molecule ligands and large proteins (and protein-ligand complexes).<br /><br /><br />Calculation of the electrostatic contributions for the binding energies in a continuous solvation energy approach imposes different problems for large and small molecules. Normally people use some kind of Generalized Born (GB) approximation. The latter is only exact for a charge in the center of a spherical cavity and thus can only be valid for a small molecule with most of the charge located within a few atoms.<br /><br />If the molecule of interest is large, most of the charges are close to the molecular surface, instead. GB approximation in its most commonly accepted form fails next to a molecular surface: the Born radius is missed by a factor of 2. This means that there can be no "classic" GB model working good both for small and large molecules!<br /><br />Binding affinity calculation requires calculation of differences between the energy of the complex (a large molecule) and the energies of the protein (another large molecule) and the ligand (a small molecule) at infinite separation.<br /><br />If a GB model is made working by careful adjusting of "bare" Born radii to fit experimental IC50 of complexes, a good sanity check would require reproduction of experimentally known solvation energies of small molecules and ions (and the other way around). The two graphs in this post show, that this is indeed possible. A relatively large error in the small molecules solvation energies shows that although the resulting model is reasonable, the obtained GB parameters are only quantitatively transferable between large and small molecules.Peter Fedichev (Quantum CTO)http://www.blogger.com/profile/06881436001010579010noreply@blogger.com0tag:blogger.com,1999:blog-6971293376725642998.post-49677851307380937072008-12-30T04:15:00.000-08:002008-12-30T04:33:39.609-08:00How much water is in a Generalized Born protein?<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiBXABkG4YZpTWJTDFKHLlYazIfaHMuw3UmiSAbma7uCzA139R3TstHzOZetlp1xD_ocg_wLpznBSX5yvhWZj20rANalc-2QFWEm6HcF_e0rPYVtm8D1o0JYYIfimzSq7lVe5XB-YFLxPWo/s1600-h/BornRadii.png"><img style="margin: 0pt 10px 10px 0pt; float: left; cursor: pointer; width: 320px; height: 237px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiBXABkG4YZpTWJTDFKHLlYazIfaHMuw3UmiSAbma7uCzA139R3TstHzOZetlp1xD_ocg_wLpznBSX5yvhWZj20rANalc-2QFWEm6HcF_e0rPYVtm8D1o0JYYIfimzSq7lVe5XB-YFLxPWo/s320/BornRadii.png" alt="" id="BLOGGER_PHOTO_ID_5285555890509649186" border="0" /></a>Born approximation is a weapon of choice for a (relatively) fast calculation of solvation energies in modeling. Although the approach is conceptually simple, it can not be correctly derived from first principles (i.e. does not correspond to a solution of electrostatic problem in a strict or even variational sense).<br /><br />In practice applications of Generalized Born models are further complicated by various approximations for calculating volume (or surface) integrals, removing atom overlaps etc. What remains left is some sort of approximation to molecular volume (surface) and the so called Born Radii for every atom.<br /><br />Each of the Born radii quantitatively shows a degree to which an atom is "buried" within the protein. The presented graph gives a simple idea to a which extent GB can even be used for description of solvation energies of a simple, model spherical protein containing approx. 1000 atoms of carbon.<br /><br />The red squares give the dependence of the Born Radii on the atom positions. The points are obtained using our own implementation of AGBNP, one of the best realizations of GB procedures available in the literature.<br /><br />The yellow curve represents exact result for a spherical protein, where GB and exact analytical expressions coinside. As one can see, AGBNP result fails to grow inwards and saturates at a very small value at <span style="font-style: italic;">r=0</span>.<br /><br />The reason for this behaviour is two-fold: first AGBNP is based on the so-called Coulomb approximation and thus can not be exact. Indeed, Coulomb approximation fails at the protein boundary and gives d(Born Radius)/dr twice as large as the exact result. This is a true problem, but it can not explain fundamentally wrong results in the protein center!<br /><br />The other problem of AGBNP (and in fact any GB model), is that the model implies a certain approximation for molecular surface and the surface may have water filled cavities inside the protein! The cavities represent (within the same model) a medium with high dielectric constant and decrease the value of the Born radii.<br /><br />To check the last assumption we searched for the water filled cavities removed them (to a certain adjustable extent). The result is represented by the blue circles and shows a clear improvement towards reproducing the exact analytical result.<br /><br />Conclusion? Dry your protein up before even attempting to use GB approximation to get a good solvation energy for a large molecule!Peter Fedichev (Quantum CTO)http://www.blogger.com/profile/06881436001010579010noreply@blogger.com0tag:blogger.com,1999:blog-6971293376725642998.post-90494062981395994672008-12-16T01:29:00.000-08:002008-12-31T07:00:23.984-08:00Video recorded from "Water as a ferroelectric..." presentation at MIPT, November 5th, 2008<center><OBJECT width="470" height="353"><PARAM name="movie" value="http://video.rutube.ru/5b924f8526b191dd900c06f76b9e0344"></PARAM><PARAM name="wmode" value="window"></PARAM><PARAM name="allowFullScreen" value="true"></PARAM><EMBED src="http://video.rutube.ru/5b924f8526b191dd900c06f76b9e0344" type="application/x-shockwave-flash" wmode="window" width="470" height="353" allowFullScreen="true" ></EMBED></OBJECT></center><br /><br /><br /><a href="http://drugdiscoverywizzards.blogspot.com/2008/11/5th-of-november-talkmipt.html">Water as a ferroelectric: anomalous properties, long range order and interactions of nano-particles in solution</a> (in Russian)Peter Fedichev (Quantum CTO)http://www.blogger.com/profile/06881436001010579010noreply@blogger.com0tag:blogger.com,1999:blog-6971293376725642998.post-61819820231272417242008-11-25T03:26:00.000-08:002008-11-25T05:51:50.514-08:002008 Quantum's technology platform update and software releasesIt has been an exciting year here in Quantum Pharmaceuticals, another great year for our highly effective small molecule drug discovery and ADMET platform development. Our work is firmly based in basic science: QUANTUM science team developed a vector field theory of water capable of describing numerous anomalous thermodynamic and dielectric of water, as well as interactions of biomolecules in aqueous environments (<span class="list-identifier"><a href="http://xxx.lanl.gov/abs/0808.0991" title="Abstract">arXiv:0808.0991</a></span>).<br /><br />The progress in our understanding of biomolecules interactions led to further accuracy improvements in our major calculation routines (IC50, solvation energy, etc.). Speed increase and sophistication of the models employed in our simulations provided better ways for false positive elimination. Direct application of our software brought up novel inhibitors of HIV integrase and gp120 proteins, human neutrophyle elastase (HNE) (see <a href="http://drugdiscoverywizzards.blogspot.com/search/label/collaboration">collaborations</a>). Massive computations made using Amazon EC2 computing platform let us develop new and refind existing ADMET models (see drug absorbtion prediction (<span class="list-identifier"><a href="http://xxx.lanl.gov/abs/0810.2617" title="Abstract">arXiv:0810.2617</a></span>) as an example).<br /><br />All the scientific advances are plugged in and available through the following releases of Quantum sofware (sold separately and in packages at discount prices):<br /><br /><span style="font-weight: bold;">q-TOX</span> - enables researches to compute toxic effects of chemicals solely from their molecular structure (LD50, MRDD, side effects) . The robust model is based on completely new approaches. While there are numerous commercially available toxicity prediction software, none offers the depth, scope and precision comparing to q-TOX. The paradigm in the q-TOX approach is based on the premise that biological activity results from the capacity of small molecules to modulate the activity of the proteome.<br /><br /><span style="font-weight: bold;">q-Mol</span> - calculates such physicochemical parameters as Solubility in H2O (g/l); Solubility in DMSO (g/l); LogP, water/octanol; Mol weight; H-bond donors; H-bond acceptors; The number of rotatable bonds;Lipinski-rule-of-5.<br /><br /><span style="font-weight: bold;">q-ADME</span> - For the first time we identified proteins, binding to which correlates well with FA and T1/2. This enabled us to simulate the active component of the ADME properties that has been the heel of Achilles for existing computational approaches still. The software predicts the following properties: Drug half-life (T1/2); Fraction of oral dose absorbed (FA); Caco-2 permeability; Volume of distribution (VD); Octanol/water distribution coefficient (LogP)<br /><br /><span style="font-weight: bold;">q-hERG</span> - a unique and innovative software, which allows you to predict from a molecule structures of compounds their inhibition constants (IC50) for hERG channels.<br /><br /><span style="font-weight: bold;">q-Albumin</span> software takes a molecular structure and calculates HSA binding constant by docking the molecule to both of the HSA active sites (Sudlow site I and Sudlow site II).Peter Fedichev (Quantum CTO)http://www.blogger.com/profile/06881436001010579010noreply@blogger.com0tag:blogger.com,1999:blog-6971293376725642998.post-13995761612887424712008-11-03T05:50:00.000-08:002008-11-05T12:11:41.941-08:005th of November talk@MIPT Interdisciplinary Seminar "Water as a ferroelectric: anomalous properties, long range order and interactions of nano-par....<p align="justify"> Moscow Instutite of Physics and Tehcnology, November 5th, 2008. "<span style="font-weight: bold;">Water as a ferroelectric: anomalous properties, long range order and interactions of nano-particles in solution</span>" (in russian)</p><br /><iframe src='http://docs.google.com/EmbedSlideshow?docid=dfjpm3gg_51897kfhvdk&size=m' frameborder='0' width='555' height='451'></iframe><br /><p align="justify">The presentation will be held in room <u>202НК</u>, 18:35 (read full announcement <a href="http://theorphys.mipt.ru/subscription/RassylMejPred/mejprs05nov2008.html">here</a>).<br /></p>Peter Fedichev (Quantum CTO)http://www.blogger.com/profile/06881436001010579010noreply@blogger.com0tag:blogger.com,1999:blog-6971293376725642998.post-68505618924628030992008-10-28T07:46:00.000-07:002008-10-28T08:45:25.472-07:00Quantum Pharmaceuticals enters collaboration with Children's Cancer Institute Australia<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEirNRP9MBthgDq7pkluFUCUrtaI7udk5VsxmyMrI63yBlOK8E6_l3Hxtqwhs4KeICxhup-9lcJSqeF29oYtIjPZfSjj83DsULMXOIQXUC9PQ4B4J4Qu6cb-Mq0zo0ylEP3IskdhUAc_8oI/s1600-h/children+cancer+institute+of+australia.JPG"><img style="margin: 0px auto 10px; display: block; text-align: center; cursor: pointer; width: 280px; height: 106px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEirNRP9MBthgDq7pkluFUCUrtaI7udk5VsxmyMrI63yBlOK8E6_l3Hxtqwhs4KeICxhup-9lcJSqeF29oYtIjPZfSjj83DsULMXOIQXUC9PQ4B4J4Qu6cb-Mq0zo0ylEP3IskdhUAc_8oI/s320/children+cancer+institute+of+australia.JPG" alt="" id="BLOGGER_PHOTO_ID_5262221160867607714" border="0" /></a><br /><br /><p style="font-family:times new roman;"><span style="font-size:100%;">Moscow, October, 28 2008</span></p><p style="font-family:times new roman;"><span style="font-size:100%;">Quantum Pharmaceuticals announce drug discovery collaboration with Children's Cancer Institute Australia's (CCIA). Under the terms of the agreement Quantum Pharmaceuticals gets access to CCIA in-house disease target data. Quantum Pharmaceuticals will contribute its technological breakthroughs and expertise in small molecule drug discovery to feed the portfolio of CCIA with new drug candidates. CCIA is to further develop the discovered inhibitors. The targets and financial terms were not disclosed.<br /></span></p><p style="font-family:times new roman;"><span style="font-size:100%;"><span style="font-size:100%;"><span style="font-weight: bold;">About Quantum Pharmaceuticals</span></span></span></p><p style="font-family:times new roman;"><span style="font-size:100%;"><span style="font-size:100%;"><span style="font-weight: bold;"></span>Quantum Pharmaceuticals is a drug discovery company based in Moscow, Russia specializing in small molecule screening and design through the use of its proprietary technology platform.</span></span></p> <p style="font-family:times new roman;"><span style="font-weight: bold;font-size:100%;" >About CCIA </span><span style="font-size:100%;"><br /></span></p><p style="font-family:times new roman;"><span style="font-size:100%;">Children's Cancer Institute Australia's (CCIA) vision is to save the lives of all children with cancer and eliminate their suffering.Our mission is to be a leader in preventing cancer, to find new ways of curing cancer in children through world-class research, to ensure the best possible quality of life for these children and their families, to share the vision with others and to increase awareness, participation and funding.</span></p>Business Developmenthttp://www.blogger.com/profile/12877884816190567351noreply@blogger.com0tag:blogger.com,1999:blog-6971293376725642998.post-5159479347715003552008-10-28T07:09:00.000-07:002008-10-28T07:40:35.445-07:00Quantum Pharmaceuticals collaborates with University of Pittsburgh on HIV drug discovery.<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiG8LIjkSUAkNrrvwISK0iKhRkSYxZS7gjgWGdWnv1YJ7ZiK0YnFLLx-9XzZbfuw3wQ35tJm2jzzYvwDccNBXLa392OXnigonJTU0Vz5_Y3KuiDM-y2XRDuvnbdujoQksfYThkuK9LvLZY/s1600-h/university+of+pittsburg.JPG"><img style="margin: 0px auto 10px; display: block; text-align: center; cursor: pointer; width: 158px; height: 149px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiG8LIjkSUAkNrrvwISK0iKhRkSYxZS7gjgWGdWnv1YJ7ZiK0YnFLLx-9XzZbfuw3wQ35tJm2jzzYvwDccNBXLa392OXnigonJTU0Vz5_Y3KuiDM-y2XRDuvnbdujoQksfYThkuK9LvLZY/s320/university+of+pittsburg.JPG" alt="" id="BLOGGER_PHOTO_ID_5262214170903948594" border="0" /></a><br /><span style=";font-family:times new roman;font-size:100%;" id="dtlview_Account Name" >Moscow, October, 20 2008<br /><br />Quantum Pharmaceuticals and University of Pittsburgh announced a drug discovery collaboration in HIV sphere. </span><span style=";font-family:times new roman;font-size:100%;" id="dtlview_Account Name" >Under the terms of agreement Quantum Pharmaceuticals gets access to the target data from University of Pittsburgh.</span><span style=";font-family:times new roman;font-size:100%;" id="dtlview_Account Name" > Quantum Pharmaceuticals</span><span style="font-size:100%;"><span style="font-family:times new roman;"> will apply its industry leading computational technology to discover novel small molecule inhibitors for this target. The University is to provide biological expertise and further develop the discovered inhibitors. The financial terms of the deal were not disclosed.<br /></span></span><span style="font-size:100%;"><span style="font-weight: bold;font-family:times new roman;" >About Quantum Pharmaceuticals<br /></span><span style="font-family:times new roman;">Quantum Pharmaceuticals is a drug discovery company based in Moscow, Russia specializing in small molecule screening and design through the use of its proprietary technology platform.<br /></span><span style="font-weight: bold;font-family:times new roman;" >About University </span></span><span style="font-weight: bold;font-family:times new roman;font-size:100%;" id="dtlview_Account Name" >of Pittsburgh</span><span style="font-size:100%;"><br /><span style="font-family:times new roman;">Founded in 1787 the University </span></span><span style=";font-family:times new roman;font-size:100%;" id="dtlview_Account Name" >of Pittsburgh</span><span style="font-size:100%;"><span style="font-family:times new roman;"> has evolved into an internationally recognized center of learning and research. The University’s 12,000 employees, including 3,800 full-time faculty members, serve about 34,000 students through the programs of 15 undergraduate, graduate, and professional schools.</span></span>Business Developmenthttp://www.blogger.com/profile/12877884816190567351noreply@blogger.com0tag:blogger.com,1999:blog-6971293376725642998.post-38790174148276636822008-10-10T00:16:00.000-07:002008-10-10T00:20:13.984-07:00q-hERG: QUANTUM's innovative approach to hERG binding calculations is updated to v 2.0Quantum Pharmaceuticals, the owner of this blog, is proud to release version 2.0 of its innovativ HERG protein binding prediction software.<br /><br /><iframe src='http://docs.google.com/EmbedSlideshow?docid=dfjpm3gg_230gw66fk4n' frameborder='0' width='410' height='342'></iframe><br /><br />QUANTUM hERG (q-hERG) screening assays is a unique and innovative computational approach, which allows you to predict from a molecule structures of compounds their inhibition constants (IC50) for hERG channels.Peter Fedichev (Quantum CTO)http://www.blogger.com/profile/06881436001010579010noreply@blogger.com0tag:blogger.com,1999:blog-6971293376725642998.post-5647215533510813512008-10-08T01:25:00.000-07:002008-10-08T04:14:30.172-07:00Making a good water model: Molecules do conformationally change when cross from a gas to water solution<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgZR0YcasYYM1EQM5aG64gX7Xg9AJEAtf2w5ZP45uP5EURIFiAM_FM9kukru2HpUTX4vfsoPM-68OrMhbB_PRCzlyyQJzb4gcaWW9gA2kTeVHPZi0vGjoKfPN9jzP6BWfY1pwh_-VPP6A4x/s1600-h/ESolvConformationalChanges.png"><img style="margin: 0pt 10px 10px 0pt; float: left; cursor: pointer;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgZR0YcasYYM1EQM5aG64gX7Xg9AJEAtf2w5ZP45uP5EURIFiAM_FM9kukru2HpUTX4vfsoPM-68OrMhbB_PRCzlyyQJzb4gcaWW9gA2kTeVHPZi0vGjoKfPN9jzP6BWfY1pwh_-VPP6A4x/s320/ESolvConformationalChanges.png" alt="" id="BLOGGER_PHOTO_ID_5254738422503018690" border="0" /></a>Solvation energy calculation is absolutely crucial for a successful binding free energy (IC50) determination. Quantum Pharmaceuticals develops aqueous solvation models and tests them against available experimental data to validate the theoretical approaches.<br /><br />The graph on the left represents two types of solvation energy calculations compared with experiments. The first series (small circles) are the energy differences on solvation for a set of molecules without conformational changes taken into account. The second set (large squares) is obtained after a single optimization run.<br /><br />The correlation with the experiment clearly improves after conformational changes calculations. Apparently this does not only mean that the model is good, it also means that the molecules do change structure when inserted into water from the gas phase.Peter Fedichev (Quantum CTO)http://www.blogger.com/profile/06881436001010579010noreply@blogger.com0tag:blogger.com,1999:blog-6971293376725642998.post-87491399772354568632008-09-25T05:53:00.000-07:002008-10-10T00:26:19.209-07:00From Biological Spectra (multiple protein binding data) to pharmacological profiling!An ideal drug cures a decease and does not kill a patient (or even lab animals in the course of preclinical testing). Usual drug discovery paradigm is based on studying a compound's properties against a specific, normally decease-related (protein) target. The ability of a compound to bind (inhibit) a specific target is called efficacy.<br /><br />Even if the efficacy is good, another important property of a compound is its toxicity. Toxicity is related to the compound physical properties, such as solubility etc, as well by its ability to bind to and hence inhibit various vital human proteins (and may be even DNA and RNA).<br /><br />Common sense suggests that an ideal compound binds its specific drug related target and does not bind to anything else. Anything in between is toxic, at least to a some extent. For example, most of important properties utilize ATP molecules, which means that human body contains a lot of ATP-bindig proteins. If you make a drug attacking an ATP-binding site of a "bad" protein, most probably, a lot of "good" and useful proteins will be also affected. In that case your compound should be toxic. This is indeed the case for many cancer drugs attacking ATP-binding sites of kinases.<br /><br />The latter statement is the foundation of our approach. Although it's quite conceptually simple, it's useless unless it can be supplemented by a meaningful mathematical model. Let us dwell into some more details to see how the whole thing can be made working.<br /><br />Let us overview important properties of a drug candidate. First there is a bunch of physical properties, such as solubility, differential solubility, LogP (namely the difference between water and lipid solubility) etc. These quantities are easy to measure, are of direct physical meaning and can be pretty easily calculated (with or without QUANTUM software).<br /><br />Another set of characteristics defines a compound ability to penetrate through cell membranes and its biochemical in liver. These are quantities deturmining bioavailability, half life, volume of distribution etc. None of such quantities can be evaluated using the simple physical properties alone. For example, drug absorbtion depends on the molecule interaction with proteins actively transporting the molecules through the cell membranes.<br /><br />The bottom line: bioavailability and other quantities require understanding of a compound binding properties to a selected number of proteins participating in a compound transport and metabolism.<br /><br />So the conclusion is that IF YOU KNOW WHICH PROTEINS ARE IMPORTANT, AND IF YOU CAN CALCULATE HOW YOUR COMPOUND BINDS TO THEM, YOU KNOW THE COMPOUND PHARMACOLOGICAL AND TOXICOLOGICAL PROPERTIES<br /><br />Now the only problem how to identify those "important" proteins.<br /><br />Fortunately, there are thousands of molecules with known properties. What we can do is the following:<br /><br />- take a molecule<br />- calculate its binding to any human protein with known 3d structure<br />- use the obtained binding affinities (numbers) as a molecule's binding profile fingerprint (the Biological Spectrum), characterizing the ability of the molecule to interact with the whole human proteome<br /><br />Now assume we know such Biological Spectra for 1000s molecules with well known properties. This means we can now datamine the fingerprints->known properites relations. The basic premise is, of course, that the molecules with similar fingerprints have similar properties.<br /><br />We have a number of proofs of such technology working. The most recent one is the <a href="http://drugdiscoverywizzards.blogspot.com/2008/09/from-binding-data-to-pharmacokinetics.html">prediction of active transport drug absorption properties for drug like molecues</a> based on the binding data against human brain hexokinase type I-related protein. We prove that the binding energy of a compound against the protein may serve to distinguish between the passively and actively transported molecules and even help to calculated the drug absorbtion quantitatevely.Peter Fedichev (Quantum CTO)http://www.blogger.com/profile/06881436001010579010noreply@blogger.com0tag:blogger.com,1999:blog-6971293376725642998.post-3013220593098159802008-09-25T05:07:00.000-07:002008-10-17T00:39:37.425-07:00From binding data to pharmacokinetics: a novel approach to active drug absorbtion predictionOral administered drugs are mainly absorbed in the small intestine. Here, depending on drug composition and size, absorption can happen through a variety of processes . Through the epithelial cells and the lamina pro- pria the drug passes from the lumen into the blood stream in the capillaries. On its way it might be metabolised, transported away from the tract where absorption is possible or accumulate in organs other than those of treatment. Besides a fundamental interest in understanding the basic mechanisms by which a drug is assimilated by the human body, the kinetics of drug absorption is also a topic of much practical interest. A detailed knowledge of this process, resulting in the prediction of the drug absorption profile, can be of much help in the drug development stage .<br /><br />To this end, several kinetic models for drug absorption within the body have been introduced (see e.g. ). They necessarily introduce some simplifications belonging to the category of the so-called three-compartment models where the substances (such as drugs or nutrients) move between three volumes (e.g. the human organs). In fact the models require two kinds of molecular properties. First are purely physical characteristics, such as solubility, differential solubility, LogP etc. These quantities are easy to measure or to calcualte, have direct physical meaning and sufficient to predict absorbtion profile of passively absorbed drugs. Actively transported molecules interact with protein transporters and therefore prediction for actively transporting compounds require a lot of separate knowledge of binding to and kinetics of the transporting proteins.<br /><br /><center><br /><iframe src="http://docs.google.com/EmbedSlideshow?docid=dfrhzg5m_0fd8cqrg4&size=m" width="555" frameborder="0" height="451"></iframe><br /></center><br /><br />The major objective of this investigation was to develop a drug absorbtion prediction approach based on entirely different paradigm, thus avoiding difficulties of both knowledge-based and QSAR-based models, and therefore capable of better predictions. Recently it was observed that experimental values of molecular activities against a large proteins set can be used for predicting broad biological effects . In this investigation we take advantage of this concept and develop a novel quntitative method for identification of actively transported drugs. To do that we performed a docking study of a few hundreds small molecules (mostly drugs) against a diversified 510 proteins set representing human proteom. Using available absorbtion data for each of the molecules we obtained a support vector classifier capable to identify proteins which affinity for drugs correlates well with the active absorption of these drugs in 81% cases. The observation helped us improve our passive absorbtion model by adding non-liner fluxes associated with the transporting protein to obtain also a quantitative model of the passively absorbed drugs.<br /><br /><span style="font-weight: bold;">Ref</span>: <span class="list-identifier"><a href="http://xxx.lanl.gov/abs/0810.2617" title="Abstract">arXiv:0810.2617</a> [<a href="http://xxx.lanl.gov/ps/0810.2617" title="Download PostScript">ps</a>, <a href="http://xxx.lanl.gov/pdf/0810.2617" title="Download PDF">pdf</a>, <a href="http://xxx.lanl.gov/format/0810.2617" title="Other formats">other</a>]</span><dl><dd> <div class="meta"> <div class="list-title"> <span class="descriptor">Title:</span> From protein binding to pharmacokinetics: a novel approach to active drug absorption prediction </div> <div class="list-authors"> <span class="descriptor">Authors:</span> <a href="http://xxx.lanl.gov/find/q-bio/1/au:+Fedichev_P/0/1/0/all/0/1">P.O. Fedichev</a>, <a href="http://xxx.lanl.gov/find/q-bio/1/au:+Kolesnikova_T/0/1/0/all/0/1">T.V. Kolesnikova</a>, <a href="http://xxx.lanl.gov/find/q-bio/1/au:+Vinnik_A/0/1/0/all/0/1">A.A. Vinnik</a> </div> <div class="list-comments"> <span class="descriptor">Comments:</span> 9 pages, 5 eps figures </div> <div class="list-subjects"> <span class="descriptor">Subjects:</span> <span class="primary-subject">Quantitative Methods (q-bio.QM)</span>; Biomolecules (q-bio.BM) </div> </div> </dd></dl>Peter Fedichev (Quantum CTO)http://www.blogger.com/profile/06881436001010579010noreply@blogger.com1tag:blogger.com,1999:blog-6971293376725642998.post-23549326110121254332008-09-25T04:22:00.000-07:002008-09-25T04:44:04.899-07:00The nature of percolation phase transition in films of hydration water around immersed bodies.<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgMEALTnZzH4qVGQotJjytRnftiZXDSQevZIjN6MCOVPr05MSLV4SGdFxef-iHAHeABwOeiN2ioPCsBwHsLH7sdlqnOkhW_7GFXpsCfgaKNHcQKErgiOMlH3VznIsB7gWZw2SVEVEEKSq9l/s1600-h/anotherstrangeform.jpeg"><img style="margin: 0pt 10px 10px 0pt; float: left; cursor: pointer;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgMEALTnZzH4qVGQotJjytRnftiZXDSQevZIjN6MCOVPr05MSLV4SGdFxef-iHAHeABwOeiN2ioPCsBwHsLH7sdlqnOkhW_7GFXpsCfgaKNHcQKErgiOMlH3VznIsB7gWZw2SVEVEEKSq9l/s200/anotherstrangeform.jpeg" alt="" id="BLOGGER_PHOTO_ID_5249923368431136946" border="0" /></a><span style="font-family:Times New Roman;font-size:100%;">In a set of molecular dynamics calculations (MD) the percolation phase transition in water layer absorbed on a body surface was revealed at definite temperature. Below this temperature the infinite network of unbroken hydrogen bonds exists. Above it this network decays on islands. This conclusion corresponds also with measurements of conduction of moisture contained disperse materials as quartz, for example: the conductivity drops almost to zero value while heating the specimens up to definite temperature. It is known that the water conductance dominates by the “estafette” mechanism in which protons are transferred over the hydrogen bonds. The breakdown of network means the conductivity drop. These phenomena are explained in the paper in frames of early published continuous vector model of polar liquids. It is shown that the immersed bodies are surrounded by the ferroelectric film, in which the dipole moments of water molecules are ordered, arranged in one direction parallel to the interface. It is the physics behind above mentioned MD results. In addition of our previous papers the stability of this ferroelectric order is proved. The character of phase transition to the paraelectric phase is discussed and its temperature is estimated that is in agreement with MD results. Below the critical temperature the polarization vector field contains the structures as “vortex-antivortex pairs”. These pairs dissociate above this temperature that means the order breaking. The boundary conditions for the polarization vector field of molecular dipole moments are derived that is necessary to enclose the vector model equations.</span><br /><span style=";font-family:Times New Roman;font-size:100%;" ><br /><span style="font-weight: bold;">Reference</span>: accepted for publication to <a href="http://www.maik.rssi.ru/cgi-perl/journal.pl?lang=eng&name=jory">Journal of Structual Chemistry (Russian Journal of)</a>, 2008<br /></span>Peter Fedichev (Quantum CTO)http://www.blogger.com/profile/06881436001010579010noreply@blogger.com0tag:blogger.com,1999:blog-6971293376725642998.post-19444081090541006412008-09-25T03:42:00.001-07:002008-09-25T03:50:31.676-07:00Spontaneous polarization of a polar liquid next to nano-scale impurities<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjmwyTMbJ4AnuK0ytaQoD4NPmfduyXxVh-VH-dpj-sfI6KkIq_lyU5wlNwSqtntVJap-3oBq55uisTARdcz9WnkV03xl-Bl6Rrphp_kbCc-Fp5ZlWKQ9YCV9p4W8oVsrZQ1uQVqqTvyqpjC/s1600-h/strangeform.jpeg"><img style="margin: 0pt 10px 10px 0pt; float: left; cursor: pointer;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjmwyTMbJ4AnuK0ytaQoD4NPmfduyXxVh-VH-dpj-sfI6KkIq_lyU5wlNwSqtntVJap-3oBq55uisTARdcz9WnkV03xl-Bl6Rrphp_kbCc-Fp5ZlWKQ9YCV9p4W8oVsrZQ1uQVqqTvyqpjC/s200/strangeform.jpeg" alt="" id="BLOGGER_PHOTO_ID_5249907645176969362" border="0" /></a><span style=";font-family:Times New Roman;font-size:100%;" >Numerous properties of water are determined by the hydrogen bonds between its molecules. Water does not form hydrogen bonds with hydrophobic materials, henceforth, dipole moments of its molecules are arranged mainly parallel to the interfaces with such substances. According to molecular dynamics calculations (MD) at such orientation molecules save the maximal number of hydrogen bonds: three of fourth. It is shown in this Letter that in the layer of water or ice next to surface the long-range order spontaneously forms: remaining parallel to the surface dipole moment vectors arrange in one direction. Some fraction of dipole moments form the vortex structures on the surface. At low temperatures the ordered state has small admixture of vortex-antivortex pairs. The interaction energy of vortexes in this pairs arises proportional to the distance between them. A definite temperature the phase transition takes place: pairs suffer the dissociation, the molecular dipole moments order disappears. This conclusion agrees with he results of MD calculations, in which the percolation phase transition was revealed in the hydrogen bond network of water molecules absorbed on a surface.</span> <p align="justify"><span style=";font-family:Times New Roman;font-size:100%;" > The spontaneous polarization of liquid induced by the immersed in it nano-size bodies (proteins, peptides, …) results in the additional long-range interaction between them that depends on their relative orientation. Polarization of liquid in this case looks like that presented in Fig.1 in agreement with MD. All mentioned MD results can not be explained in frames of standard continuous scalar theory of water. These phenomena were analyzed here in frames of continuous vector model of polar liquids applications of which looks like promising to speed the simulations of macromolecular complexes.<br /></span></p><p align="justify"><span style="font-weight: bold;">Reference</span>: <span class="list-identifier"><a href="http://xxx.lanl.gov/abs/cond-mat/0601129" title="Abstract">arXiv:cond-mat/0601129</a> [<a href="http://xxx.lanl.gov/ps/cond-mat/0601129" title="Download PostScript">ps</a>, <a href="http://xxx.lanl.gov/pdf/cond-mat/0601129" title="Download PDF">pdf</a>, <a href="http://xxx.lanl.gov/format/cond-mat/0601129" title="Other formats">other</a>]</span></p><dl><dd> <div class="meta"> <div class="list-title"> <span class="descriptor">Title:</span> Long-Range Order and Interactions of Macroscopic Objects in Polar Liquids </div> <div class="list-authors"> <span class="descriptor">Authors:</span> <a href="http://xxx.lanl.gov/find/cond-mat/1/au:+Fedichev_P/0/1/0/all/0/1">P.O. Fedichev</a>, <a href="http://xxx.lanl.gov/find/cond-mat/1/au:+Menshikov_L/0/1/0/all/0/1">L.I. Men'shikov</a> </div> <div class="list-comments"> <span class="descriptor">Comments:</span> 11 pages, 6 figures </div> <div class="list-subjects"> <span class="descriptor">Subjects:</span> <span class="primary-subject">Soft Condensed Matter (cond-mat.soft)</span>; Chemical Physics (physics.chem-ph); Biomolecules (q-bio.BM) </div> </div> </dd></dl><p align="justify"><span style=";font-family:Times New Roman;font-size:100%;" >Accepted for publication in <a href="http://www.maik.rssi.ru/cgi-perl/journal.pl?name=physcha&page=main">Journal of Physical Chemistry A (Russian Journal of),</a> 2009<br /></span></p>Peter Fedichev (Quantum CTO)http://www.blogger.com/profile/06881436001010579010noreply@blogger.com0tag:blogger.com,1999:blog-6971293376725642998.post-43400346445402791202008-09-25T03:12:00.000-07:002008-09-25T03:49:48.537-07:00What's an ultimate value of reversible drug binding constant?<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjW3RsP6ryQcJuIeWZQD5HoFSFqXnpvRpeXAtDc69xEY5hY_B3hhP2WDvrqpKgrf8dws_M3jrHrxyvIMFxGjhmQWbAObjyMu0dhhNYGRZ891NLzCMbPuJS1VSJGHf533NfInpY3Ysb3b0mM/s1600-h/viscfluid.jpeg"><img style="margin: 0pt 10px 10px 0pt; float: left; cursor: pointer;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjW3RsP6ryQcJuIeWZQD5HoFSFqXnpvRpeXAtDc69xEY5hY_B3hhP2WDvrqpKgrf8dws_M3jrHrxyvIMFxGjhmQWbAObjyMu0dhhNYGRZ891NLzCMbPuJS1VSJGHf533NfInpY3Ysb3b0mM/s320/viscfluid.jpeg" alt="" id="BLOGGER_PHOTO_ID_5249900154061475986" border="0" /></a>Traditional opinion is that a good drug must have a high value of the absolute meaning of the binding energy with target protein in order to prevent the thermal dissociation of the drug-protein complex. In this case an essential deformation of protein arises, which has to be taken into account in developing different models of protein-small molecule and protein-protein interaction, and computing affinity constants in drug discovery in-silico methods. The effect of essential perturbation of protein molecule is ignored in standard computational methods of drug design that can contribute a large mistake to results of calculation, to binding energy, for example.<br />To demonstrate the existence of the ultimate value of the binding energy two models are considered: macroscopic and microscopic, both giving the same conclusions: the critical value of absolute meaning of binding energy is 50-100kJ/M<a name="0.1_graphic04"></a>. If the binding energy exceeds this value, then drug essentially perturbs protein configuration. In a microscopic picture this perturbation is a sequence of irreversible conformational transitions in protein body. In a macroscopic one it is an inelastic deformation of a protein substance. Our estimation agrees with the experimental value (<a name="0.1_graphic05"></a>50 kJ /M) of the ultimate energy that can be stored in a protein molecule without its destruction.<br />The existence of the critical value of binding energy should be accounted in structure based drug design methods where protein molecule is considered in an elastic deformation approximation.<br /><br /><span style="font-weight: bold;">Reference</span>: accepted in <a href="http://www.maik.rssi.ru/cgi-perl/journal.pl?name=biophys&page=main">Russian Journal of Biophysics</a>, 2008Peter Fedichev (Quantum CTO)http://www.blogger.com/profile/06881436001010579010noreply@blogger.com0tag:blogger.com,1999:blog-6971293376725642998.post-50104284173895238262008-08-20T05:10:00.001-07:002008-09-25T06:01:59.323-07:00Quantum LogP module (part of q-Mol package) has been benchmarked by vcclab.orgQuantum LogP module (part of q-Mol package) has been reviewed by R. Mannhold et al. (vcclab.org) in <a href="http://www3.interscience.wiley.com/journal/121371854/abstract">"Calculation of Molecular Lipophilicity: State-of-the-Art and Comparison of Log P Methods on More Than 96,000 Compounds"</a>. From the manuscript:<br /><br />"<span style="font-style: italic;">Quantum LogP, developed by Quantum Pharmaceuticals, uses another quantum-chemical model to calculate the solvation energy. Like in COSMO-RS, the authors do not explicitly consider water molecules but use a continuum solvation model. However, while the COSMO-RS model simplifies solvation to interaction of molecular surfaces, the new vector-field model of polar liquids accounts for short-range (H-bond formation) and long-range dipole–dipole interactions of target and solute molecules Quantum LogP calculated log P for over 900 molecules with an RMSE of 0.7 and R2 of 0.94</span>".Peter Fedichev (Quantum CTO)http://www.blogger.com/profile/06881436001010579010noreply@blogger.com0tag:blogger.com,1999:blog-6971293376725642998.post-63483159063822564662008-08-18T00:01:00.000-07:002008-09-25T03:27:31.964-07:00Ferro-electric phase transition in a polar liquid and the nature of lambda-transition in supercooled water<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEheCGuRMS73ppjoV3txgXPowIGWa-h5bmF6ECSWaATaSC5YN1x0yHyX4zb9oIfJOJxo1OWXy7e7J0O6jJ6Qm3SS9h6mOtH7S0OGHv4Ja4josTKh0r-bdav7JCljjwhrptiZc7z-f2hxp02y/s1600-h/watersphere.jpg"><img style="margin: 0pt 10px 10px 0pt; float: left; cursor: pointer;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEheCGuRMS73ppjoV3txgXPowIGWa-h5bmF6ECSWaATaSC5YN1x0yHyX4zb9oIfJOJxo1OWXy7e7J0O6jJ6Qm3SS9h6mOtH7S0OGHv4Ja4josTKh0r-bdav7JCljjwhrptiZc7z-f2hxp02y/s320/watersphere.jpg" alt="" id="BLOGGER_PHOTO_ID_5235749664463078418" border="0" /></a>Water is a major and all-important example of a strongly interacting polar liquid. Dielectric properties of water surrounding nano-scale objects pose a fundamentally important problem in physics, chemistry, structural biology and in silica drug design. The issue of temperature dependence of dielectric constant, the role of fluctuations and a possibility of a ferro-electric phase transition in a polar liquid is fairly old . It attracted a new attention when a new phase transition (so called lambda-transition) was observed in supercooled water at critical temperatures between T_{c}=228K and T_{c}=231.4K . Isothermal compressibility, density, diffusion coefficient, viscosity and static dielectric constant \epsilon and other quantities diverge as T_{c} is approached, which is signature of a second order phase transition. The singularity of \epsilon is a feature of a ferro-electric transition . However, given a complexity of interactions between water molecules, the physical picture behind this phenomenon is not entirely clear . In the phase transition is explained as a formation of a rigid network of hydrogen bonds. On the other hand a ferro-electric hypothesis was also proposed and supported by molecular-dynamics simulations (MD). For example, a ferro-electric liquid phase was observed in a model of the so called ``soft spheres'' with static dipole moments . In fact, the existence of a ferro-electric phase appears to be model independent: domains where formed both in MD calculations with hard spheres with point dipoles and with soft spheres with extended dipoles .<br /><br />In the our latest publication, <a href="http://xxx.lanl.gov/abs/0808.0991">Ferro-electric phase transition in a polar liquid and the nature of lambda-transition in supercooled water</a>, we develop two related approaches to calculate free energy of a polar liquid. We show that long range nature of dipole interactions between the molecules leads to para-electric state instability at sufficiently low temperatures and to a second-order phase transition. We establish the transition temperature, T_{c}, both within mean field and ring diagrams approximation and demonstrate that the ferro-electric transition is a sound physical explanation behind the experimentally observed \lambda-transition in supercooled water. Finally we discuss dielectric properties, the role of fluctuations and establish connections with earlier phenomenological models of polar liquids.<br /><br /><span style="font-weight: bold;">Reference</span>: <span class="list-identifier"><a href="http://xxx.lanl.gov/abs/0808.0991" title="Abstract">arXiv:0808.0991</a> [<a href="http://xxx.lanl.gov/ps/0808.0991" title="Download PostScript">ps</a>, <a href="http://xxx.lanl.gov/pdf/0808.0991" title="Download PDF">pdf</a>, <a href="http://xxx.lanl.gov/format/0808.0991" title="Other formats">other</a>]</span><dl><dd> <div class="meta"> <div class="list-title"> <span class="descriptor">Title:</span> Ferro-electric phase transition in a polar liquid and the nature of \lambda-transition in supercooled water </div> <div class="list-authors"> <span class="descriptor">Authors:</span> <a href="http://xxx.lanl.gov/find/cond-mat/1/au:+Fedichev_P/0/1/0/all/0/1">P.O. Fedichev</a>, <a href="http://xxx.lanl.gov/find/cond-mat/1/au:+Menshikov_L/0/1/0/all/0/1">L.I. Menshikov</a> </div> <div class="list-comments"> <span class="descriptor">Comments:</span> 4 pages, 1 eps figure </div> <div class="list-subjects"> <span class="descriptor">Subjects:</span> <span class="primary-subject">Statistical Mechanics (cond-mat.stat-mech)</span>; Soft Condensed Matter (cond-mat.soft) </div> </div> </dd></dl>Peter Fedichev (Quantum CTO)http://www.blogger.com/profile/06881436001010579010noreply@blogger.com0tag:blogger.com,1999:blog-6971293376725642998.post-63574820561503512882008-06-15T08:11:00.000-07:002008-10-28T08:44:37.296-07:00Quantum Pharmaceuticals announce collaboration with University of Colorado at Boulder<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgV9jE5HgU8ZCMKOhRwv2zqMQ4mcXzVvte3Ang7XNEXiP5TGpgwlkTR9WEU4WSP7xNHfqr8BEgnFhvvDnbXir-F6D-OtDzvdAHGM8wH9vbE8e8Rb9skm2xYmr-6KOHhnnJidej_siim9E0/s1600-h/university+of+colorado.JPG"><img style="margin: 0px auto 10px; display: block; text-align: center; cursor: pointer; width: 221px; height: 241px;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgV9jE5HgU8ZCMKOhRwv2zqMQ4mcXzVvte3Ang7XNEXiP5TGpgwlkTR9WEU4WSP7xNHfqr8BEgnFhvvDnbXir-F6D-OtDzvdAHGM8wH9vbE8e8Rb9skm2xYmr-6KOHhnnJidej_siim9E0/s320/university+of+colorado.JPG" alt="" id="BLOGGER_PHOTO_ID_5262227959356061138" border="0" /></a><br /><span style="font-size:100%;"><span style="font-family: times new roman;">Moscow, July 15 2008<br /></span><span style="font-family: times new roman;">Quantum Pharmaceuticals announce drug discovery collaboration with University of Colorado at Boulder. Under the terms of agreement Quantum Pharmaceuticals will apply its state-of-the-art in-house drug discovery technology to discover novel small molecule inhibitors in inflammation area. CU-Boulder is to further develop the discovered inhibitors. The targets and financial terms were not disclosed.</span><span style="font-family: times new roman; font-weight: bold;"><br />About Quantum Pharmaceuticals</span><br /><span style="font-family: times new roman;">Quantum Pharmaceuticals is a drug discovery company based in Moscow, Russia specializing in small molecule screening and design through the use of its proprietary technology platform.</span><br /><span style="font-family: times new roman; font-weight: bold;">About CU-Boulder<br /></span><span style="font-family: times new roman;">As the flagship university of the state of Colorado, CU-Boulder is a dynamic community of scholars and learners. As one of 34 U.S. public institutions belonging to the prestigious Association of American Universities (AAU) – and the only member in the Rocky Mountain region – we have a proud tradition of academic excellence, with four Nobel laureates and more than 50 members of prestigious academic academies. CU-Boulder has blossomed in size and quality since we opened our doors in 1877 – attracting superb faculty, staff, and students and building strong programs in the sciences, engineering, business, law, arts, humanities, education, music, and many other disciplines. Today, with our sights set on becoming the standard for the great comprehensive public research universities of the new century, we strive to serve the people of Colorado and to engage with the world through excellence in our teaching, research, creative work, and service.</span><br /><br /></span>Business Developmenthttp://www.blogger.com/profile/12877884816190567351noreply@blogger.com0tag:blogger.com,1999:blog-6971293376725642998.post-67033987392690482072008-06-06T22:02:00.001-07:002008-12-13T02:09:37.225-08:00Docking validation study: PDK1-kinase (oncology)<a onblur="try {parent.deselectBloggerImageGracefully();} catch(e) {}" href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEii18MSp4Lmli_TXL-x-u245Fpf815V6IkDmnahqEcJJIomQSYC5-xrW8IbZC8MrT6so_rSNwxHYhxZYXeEAf9K2v4KWIeRDhZdAbIg6EeI7jW5bwPQZW6C1iEvTFTC5A33Jd6rvk9a8Hgk/s1600-h/pdk1.png"><img style="margin: 0pt 10px 10px 0pt; float: left; cursor: pointer;" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEii18MSp4Lmli_TXL-x-u245Fpf815V6IkDmnahqEcJJIomQSYC5-xrW8IbZC8MrT6so_rSNwxHYhxZYXeEAf9K2v4KWIeRDhZdAbIg6EeI7jW5bwPQZW6C1iEvTFTC5A33Jd6rvk9a8Hgk/s400/pdk1.png" alt="" id="BLOGGER_PHOTO_ID_5209000677262053090" border="0" /></a>Following the <a href="http://drugdiscoverywizzards.blogspot.com/2008/06/docking-validation-study-classic.html">classic thrombine study</a>, we catch up with a more important target: PDK1 kinase.<br /><p><b>Pyruvate dehydrogenase kinase, isozyme 1</b>, also known as <b>PDK1</b>, is a human <a href="http://en.wikipedia.org/wiki/Gene" title="Gene">gene</a>.<span style="text-decoration: underline;"></span>It codes for an <a href="http://en.wikipedia.org/wiki/Isozyme" title="Isozyme">isozyme</a> of <a href="http://en.wikipedia.org/wiki/Pyruvate_dehydrogenase_kinase" title="Pyruvate dehydrogenase kinase">pyruvate dehydrogenase kinase</a> (PDK).<a href="http://en.wikipedia.org/wiki/Pyruvate_dehydrogenase" title="Pyruvate dehydrogenase">Pyruvate dehydrogenase</a> (PDH) is a part of a <a href="http://en.wikipedia.org/wiki/Mitochondria" class="mw-redirect" title="Mitochondria">mitochondrial</a> multienzyme complex that catalyzes the oxidative decarboxylation of pyruvate and is one of the major enzymes responsible for the regulation of homeostasis of carbohydrate fuels in mammals. The enzymatic activity is regulated by a <a href="http://en.wikipedia.org/wiki/Phosphorylation" title="Phosphorylation">phosphorylation</a>/dephosphorylation cycle. Phosphorylation of PDH by a specific pyruvate dehydrogenase kinase (PDK) results in inactivation.</p><p>There are no as much known inhibitors as for thrombine. BindingDB gives a few more than 70 compounds with measured binding affinities, all relatively strong binders, many of them similar to each other. We run our QUANTUM software to perform docking and the affinity calculations. The results are represented on the graph and demonstrate a solid correlation. In fact the correlation shows QUANTUM's ability to identify strong binders and distinguish between similar compounds (selectivity).<br /></p>Peter Fedichev (Quantum CTO)http://www.blogger.com/profile/06881436001010579010noreply@blogger.com1