Mrinal Shekhar
Transforming Early-Stage Drug Discovery Through integration of Machine Learning and Structure-Based Approaches
Abstract:
Recent advances in computational approaches have transformed early-stage drug discovery, enabling more efficient identification of promising therapeutic candidates. This talk explores the synergistic application of machine learning and physics-based methods for hit discovery and lead optimization, with a focus on targeting complex protein-protein interfaces.
We present our computational approach through multiple case studies, highlighting a key innovation: the development of pharmacophore models through systematic peptide mutation to non-natural amino acids. This strategy is demonstrated in targeting the challenging E6-P53 protein-protein interaction, where mapping critical binding interactions through peptide modifications led to a comprehensive pharmacophore model that guided small molecule PPI inhibitor discovery.
Our platform integrates active learning strategies to efficiently sample the expanded chemical landscape. Model predictions inform experimental prioritization, while new data continuously refines our computational models. Through these case studies, we examine both the transformative potential and current limitations of computational methods in modern drug discovery.
Speaker: Mrinal Shekhar, Broad Institute (Boston)
Dr. Mrinal Shekhar leads the Computer Aided Drug Design Group at the Broad Institute's Center for the Development of Therapeutics (CDoT), where he combines machine learning and molecular dynamics to study protein dynamics at atomic resolution. His research integrates structural biology, proteomics, and computational methods to advance drug discovery.
At CDoT, his team develops physics-based and ML approaches for hit identification and lead optimization, working closely with medicinal chemists and structural biologists to understand protein-drug interactions and allosteric effects.
Previously, as a postdoctoral researcher at AstraZeneca's oncology unit, he developed CryoFold, an innovative method for generating protein structures from CryoEM maps using molecular dynamics. Dr. Shekhar holds a Ph.D. in biophysics from the University of Illinois at Urbana-Champaign and an M.S. in chemistry from IISER Mohali.
Host: Pratyush Tiwary
Seminars start at 4:00 pm, and refreshments will be served at 3:45 pm. All seminars are held in the Conference Room (1116) of the Institute for Physical Science and Technology (IPST) Building (Bldg #085) unless otherwise noted.