Join our first miniWEBINAR of 2025 on Opening up the druggable universe one cryptic pocket at a time presented by David LeBard, Head of Enhanced Sampling at OpenEye, Cadence Molecular Sciences, speaking about a computational workflow to validate difficult-to-drug protein targets.
About this session:
Unfortunately, a number of proteins involved in many life-threatening diseases have eluded inhibition by small molecule drugs because a suitable binding pocket could not be found. One classic example is the KRAS protein, which is a GTPase involved in more than 10% of all human cancers, yet remained undrugged for over 30 years despite immense efforts by academic and industrial researchers to find a viable pocket. A breakthrough occurred in 2013 with the uncovering of the so-called Switch-II pocket as a possible site for therapeutic design. This discovery has since led to two FDA-approved drugs for KRAS, and several other KRAS inhibitors are in advanced clinical trials. To help expand the druggable proteome to include difficult-to-drug targets like KRAS, we have developed a computational chemical biology workflow that allows straightforward assessment of possible binding pockets in a protein. Requiring only a single structure as input (experimental or computed), our automated workflow uses weighted ensemble path sampling to generate rare protein conformations that are analyzed to identify residues that cooperatively form pockets. The workflow can uncover pockets that form either by conformational selection of rare protein states or through an induced-fit mechanism by a probe molecule. Putative pockets are then ranked for druggability using a neural network model estimator of their potential binding affinity. In this webinar we present a proof-of-concept study on the Switch-II pocket in KRAS, a large-scale retrospective prediction of known cryptic pockets, and preliminary work on distinguishing genuine therapeutic targets from 'decoy' proteins.
This session will be presented by David LeBard, Ph.D., Head of Enhanced Sampling Group at OpenEye, Cadence Molecular Sciences. David earned a Ph.D. in Theoretical Chemistry in 2008 at Arizona State University studying protein electron transfer theory under Dmitry Matyushov. After a postdoc with Michael Klein at the University of Pennsylvania & Temple University working on problems of protein-ligand binding and micellar self-assembly, David accepted a tenure track faculty position in the Department of Chemistry and Biochemistry at Yeshiva University. After a few years David left academia for industry to work on free energy perturbation calculations and MD methods. David joined OpenEye in 2016 and since then has co-developed our Spruce protein preparation tool, worked on various biomodeling-related toolkits, and most recently led the development of Orion® floes for permeability prediction, protein ensemble sampling, and cryptic pocket detection.
therapeutic targets from 'decoy' proteins.
Webinar Details:
📣 Title: Opening up the druggable universe one cryptic pocket at a time
📆 Date: January 30, 2025
⏰ Time: 11-11:30 am EST
We look forward to having you join our miniWEBINAR. Can’t attend? Register anyway and we’ll send you a recording after the webinar!