Quantum Pharmaceuticals announce collaboration with University of Colorado at Boulder

Moscow, July 15 2008
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.
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 CU-Boulder
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.

Docking validation study: PDK1-kinase (oncology)

Following the classic thrombine study, we catch up with a more important target: PDK1 kinase.

Pyruvate dehydrogenase kinase, isozyme 1, also known as PDK1, is a human gene.It codes for an isozyme of pyruvate dehydrogenase kinase (PDK).Pyruvate dehydrogenase (PDH) is a part of a mitochondrial 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 phosphorylation/dephosphorylation cycle. Phosphorylation of PDH by a specific pyruvate dehydrogenase kinase (PDK) results in inactivation.

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).

Docking validation study: classic example, thrombine

The Figure on the left represents a docking study of more than 200 molecules with known activity on thrombin. The protein is a well known target ....

We have extracted the binding data from the BindingDB database and docked all the molecules onto a single (of a few available) 3D structure (2cn0 from the pdb databank).

The figure represents graphically the results of the research. The calculated and the measured activities are well correlated. Strong binders are indeed identified as strong binders (left bottom part of the graph). The accuracy of the predictions is quite good (see our discussion on the quality of the biological data here and here).

The results of the calculations can be conveniently summarized in terms of confidentiality matrix. Normally a first screen of novel compounds is performed at a certain concentration to distinguish between the active and non-active compounds. Let's take a standard, 1muM (~-35kJ/M) activity, as a separation cut-off. Then the confidence matrix has the following elements:

• Experimentally active, Predicted active: 29 molecules
• Experimentally n-active, Predicted active: 15 molecules (false positives)
  
• Experimentally active, Predicted n-active: 8 molecules (false negatives)
  
• Experimentally n-active, Predicted n-active: 156 molecules