Protein-protein interactions as new targets for drug design: virtual and experimental approaches.
Protein-protein and protein-ligand interactions play a central role in biochemical reactions, and understanding these processes is an important task in different fields of biomedical science and drug discovery. Proteins often work in complex assemblies of several macromolecules and small ligands. The structural and functional description of protein-protein interactions (PPI) is very important for basic-, as well as applied research. The interface areas of protein complexes have unique structure and properties, so PPI represent prospective targets for a new generation of drugs. One of the key targets of PPI inhibitors are oligomeric enzymes. This report shows interactive links between virtual and experimental approaches in a total pipeline "from gene to drug" and using Surface Plasmon Resonance technology for experimentally assessing PPI. Our research is conducted on two oligomeric enzymes -- HIV-1 protease (HIVp) (homo-dimer) and bacterial L-asparaginase (homo-tetramer). Using methods of molecular modeling and computational alanine scanning we obtained structural and functional description of PPI in these two enzymes. We also presented a real example of application of integral approach in searching inhibitors of HIVp dimerization -- from virtual database mining up to experimental testing of lead compounds.
Ivanov
Alexis S
AS
V.N.Orechovich Institute of Biomedical Chemistry RAMS, Pogodinskaya str. 10, Moscow, 119121, Russia. alexei.ivanov@ibmc.msk.ru
Gnedenko
Oksana V
OV
Molnar
Andrey A
AA
Mezentsev
Yury V
YV
Lisitsa
Andrey V
AV
Archakov
Alexander I
AI
D001215:Asparaginase / Q000737:chemistry*; D001665:Binding Sites; D003198:Computer Simulation; D016503:Drug Delivery Systems / Q000379:methods; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D016333:HIV Protease / Q000737:chemistry*; D008956:Models, Chemical; D011485:Protein Binding; D025941:Protein Interaction Mapping / Q000379:methods*; D020539:Sequence Analysis, Protein / Q000379:methods*
D004791:Enzyme Inhibitors; D016333:HIV Protease; D001215:Asparaginase