The number of protein structures in the Protein Data Bank is over 107 thousand and even the most recalcitrant to crystallization membrane proteins, G-protein coupled receptors (GPCRs) and channels, are no longer out of reach. These structures are converted into a collection of flexible small molecule binding pockets, the Pocketome, together with co-crystallized ligands, and converted to specific ‘dockable’ three-dimensional models. These 3D and 2D data can be used to build accurate models for predicting activity and polypharmacology of compounds and designing efficient libraries with specific binding and safety profiles. The Pocketome derived models can also be used to raise alerts concerning possible adverse effects, or, in some cases identify targets of a phenotypic screen. The models can be assembled into the organismal Pocketome models, enriched from the homologous proteins and cross-compared. Further extension of the set with homology models requires improved techniques and force fields for sequence-structure alignments, and prediction of flexible ends and loops. The combined platform of experimentally identified and predicted pockets enriched with high quality models, activity data and organized into organismal sets provides a new powerful instrument for biological discovery and chemical design.
Dr. Ruben Abagyan is a Professor in the Skaggs School of Pharmacy at the University of California, San Diego, which he joined in 2009. He received his Master’s degree in molecular physics from the Moscow Institute of Physics and Technology and his Ph.D. in molecular modeling and biophysics from the Moscow State University. At the European Molecular Biology Laboratory in Heidelberg he co-developed internal coordinate mechanics and docking approach (ICM). He headed computational biology and chemistry laboratories and cores at the Skirball Institute of New York University, Novartis Institute in La Jolla, Scripps Research Institute and San Diego Supercomputer Center, founded Molsoft company, and served on boards of several biotechnology companies. Currently Dr. Abagyan serves on steering or review committees in Switzerland, UK-EBI and Hong Kong. He authored and co-authored over 240 papers and book chapters, received two CapCure awards, and Princess Diana Award and medal in Sydney, Australia.