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The Flexible Pocketome Engine for Structural Chemogenomics

Summary: Chapter 11
The Flexible Pocketome Engine for Structural
Ruben Abagyan and Irina Kufareva
Biological metabolites, substrates, cofactors, chemical probes, and drugs bind to flexible pockets in mul-
tiple biological macromolecules to exert their biological effect. The rapid growth of the structural data-
bases and sequence data, including SNPs and disease-related genome modifications, complemented by
the new cutting-edge 3D docking, scoring, and profiling methods has created a unique opportunity to
develop a comprehensive structural map of interactions between any small molecule and biopolymers.
Here we demonstrate that a comprehensive structural genomics engine can be built using multiple
pocket conformations, experimentally determined or generated with a variety of modeling methods,
and new efficient ensemble docking algorithms. In contrast to traditional ligand-activity-based engines
trained on known chemical structures and their activities, the structural pocketome and docking engine
will allow prediction of poses and activities for new, previously unknown, protein binding sites, and new,
previously uncharacterized, chemical scaffolds. This de novo structure-based activity prediction engine
may dramatically accelerate the discovery of potent and specific therapeutics with reduced side effects.
Key words: Pocketome, Chemical biology, Flexible docking, Ensemble docking, Drug screening,
Activity prediction, SCARE algorithm, Binding site, Virtual ligand screening
Understanding the interactions of all possible chemicals with all


Source: Abagyan, Ruben - School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego


Collections: Biology and Medicine