How much water is in a Generalized Born protein?

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).

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.

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.

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.

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 r=0.

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!

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.

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.

Conclusion? Dry your protein up before even attempting to use GB approximation to get a good solvation energy for a large molecule!

Video recorded from "Water as a ferroelectric..." presentation at MIPT, November 5th, 2008

Water as a ferroelectric: anomalous properties, long range order and interactions of nano-particles in solution (in Russian)

2008 Quantum's technology platform update and software releases

It 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 (arXiv:0808.0991).

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 collaborations). Massive computations made using Amazon EC2 computing platform let us develop new and refind existing ADMET models (see drug absorbtion prediction (arXiv:0810.2617) as an example).

All the scientific advances are plugged in and available through the following releases of Quantum sofware (sold separately and in packages at discount prices):

q-TOX - 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.

q-Mol - 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.

q-ADME - 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)

q-hERG - a unique and innovative software, which allows you to predict from a molecule structures of compounds their inhibition constants (IC50) for hERG channels.

q-Albumin 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).

5th of November talk@MIPT Interdisciplinary Seminar "Water as a ferroelectric: anomalous properties, long range order and interactions of nano-par....

Moscow Instutite of Physics and Tehcnology, November 5th, 2008. "Water as a ferroelectric: anomalous properties, long range order and interactions of nano-particles in solution" (in russian)

The presentation will be held in room 202НК, 18:35 (read full announcement here).

Quantum Pharmaceuticals enters collaboration with Children's Cancer Institute Australia

Moscow, October, 28 2008

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.

About Quantum Pharmaceuticals

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.

About CCIA

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.

Quantum Pharmaceuticals collaborates with University of Pittsburgh on HIV drug discovery.

Moscow, October, 20 2008

Quantum Pharmaceuticals and University of Pittsburgh announced a drug discovery collaboration in HIV sphere. Under the terms of agreement Quantum Pharmaceuticals gets access to the target data from University of Pittsburgh. Quantum Pharmaceuticals 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.
About Quantum Pharmaceuticals
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.
About University of Pittsburgh
Founded in 1787 the University of Pittsburgh 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.

q-hERG: QUANTUM's innovative approach to hERG binding calculations is updated to v 2.0

Quantum Pharmaceuticals, the owner of this blog, is proud to release version 2.0 of its innovativ HERG protein binding prediction software.



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.