Dr. Vsevolod Katritch
Assistant Professor, USC Dept. of Biological Sciences, QCB
GPCR modeling: from structure to function to rational design of new receptors and ligands
Thursday, October 1 @ 2 PM
Zoom Meeting ID: 984 8270 9945 | Passcode: 329869
Abstract: Comprising the largest protein superfamily in human, 800 G-protein Coupled Receptors (GPCRs) play key regulatory roles in most physiological processes and serve as a target for about a third of all therapeutic drugs. Over the last few years, a flow of structural information from crystallography and cryo-EM helped to establish a solid framework for computational modelling inquiry into GPCR functional mechanisms and 3D pharmacology of GPCR ligands. The quantitative understanding of atomistic details of GPCR structure-function is also directly applicable to the rational design of both receptors and ligands with new properties. This talk will describe several new approaches to GPCR computational modelling and design developed in my lab. Using sequence-based, structure-based, and machine-learning approaches we developed the CompoMug software for predicting stabilizing mutations in GPCRs, which has already helped to crystallize more than a dozen receptors. Discovery of new allosteric co-factors, including highly conserved sodium ion in the center of the 7TM bundle in Class A GPCRs, has opened a venue for rational design of highly potent bitopic ligands with unusual signalling properties. This design approach has yielded novel opioid receptor probes and can be applied to many GPCRs. Finally, we develop a conceptually new Virtual SYNTon Hierarchical Enumeration Screening approach, V SYNTHES, which enables fast and accurate screening in combinatorial REadily AvailabLe (REAL) chemical space as large as 10 Billion compounds and more. Tested in prospective screening for Cannabinoid receptor ligands, V-SYNTHES yielded 20 novel submicromolar ligands, while showing more than 100-fold improved speed and better hit rates than the traditional virtual ligand screening. The approach is scalable to the rapidly growing combinatorial libraries beyond 1010-1013 compounds, yielding better hits and also streamlining their optimization. We apply these computational tools to the key receptors in inflammation, sleep and pain modulation pathways, facilitating discovery of novel GPCR ligands with desirable functional profiles as molecular probes and lead candidates.
Hosts: Dr. Charles McKenna and Dr. Remo Rohs
