Protein flexibilty and ligand interaction complementarity example

Human neutrophil elastase complexed with an inhibitor (gw475151) studied with QUANTUM normal modes analysis tools. The video shows the inhibitor (red licorice) remains in a strongly interacting position regardless of the protein most probable motion:

Most of available docking software performs free energy scoring for different ligands positions on the same rigid protein structure. The validity of such procedure can not be easily asserted. Not only different PDB Data Bank structures of the same protein are different, NMR studies show often impressive protein flexibility and thus uncertainty in the protein atoms positions. The necessity to compensate for the lack of the structure information makes scoring functions developers utilize smooth energy scores corresponding to some kind of coarse grain approximation for the protein-ligand interactions. Such an averaging leads to inability to recover fine details of interactions and hence to lack of selectivity and false postives, i.e. hits with binding constants actually lower than predicted.

The movie above helps explain this situation. While a scoring function could suggest an accurate value for the particular ligand docked in the experimentally observed position, the scores for "hits" overlapping with the protein motion could be the same good or better, but false, since the protein position extracted from the PDB data represents only a single member of the statistical ensemble. Mathematically speaking the ligand gw475151 does not only have a good interaction energy (enthalpy), but also remains complementary to the protein pocket in spite of sufficiently large protein displacements (has a low entropy loss associated with the protein degrees of freedom).

Materials and methods:The initial information about the protein-ligand structure is taken from 1h1b PDB entry. The ligand was taken out and protein was let to relax in QUANTUM continuum water (see cond-mat/0601129). After a sufficiently long molecular dynamics simulation the protein motion has been analyzed and the lowest normal mode (highest amplitude protein motion) was separated. The ligand is then placed back at a fixed position to highlight dynamic overlap between the ligand steric interactions and the protein motion.

HIV-1 integrase drug discovery collaboration

Moscow, September, 28 2006

Quantum Pharmaceuticals and A.N. Belozersky Institute of Physico-Chemical Biology entered drug discovery collaboration aimed to discovery of novel small molecule inhibitors of HIV-1 integrase. HIV-1 integrase is one of the most promising targets in HIV drug discovery. Under the terms of the agreement Quantum Pharmaceuticals will apply its indystry leading drug discovery technology platform to identify novel classess of HIV-1 integrase inhibitors. The Institute is to evaluate the discovered compounds and contribute into its further research and development.

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.

Quantum Pharmaceuticals and Institute of Pulmonology entered COPD drug discovery collaboration.

Moscow, June, 18 2006 Quantum Pharmaceuticals and Federal State Institution "Scientific Research Institute of Pulmonology of Roszdrav" entered COPD collaboration.

Quantum Pharmaceuticals and Federal State Institution "Scientific Research Institute of Pulmonology of Roszdrav» announced drug discovery collaboration. The collaboration is aimed on the application of Quantum Pharmaceuticals’ proprietary drug discovery technology to identify novel small molecules inhibitors of Human Neutrophil Elastase.

Under the terms of agreement Institute will be responsible for biological evaluation and further development of discovered inhibitors.


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.