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Shannon Smith

Shannon Smith PDI19
Predoctoral Fellowship in Informatics, 2019 Vanderbilt University

Pipeline for Ultra-Large Virtual Screening Using RosettaGPCR and DOCK: A Test Case for PAR4 Inhibitor Development


Structure-based drug discovery has become a valuable tool during early stages in pharmacological development campaigns. This project develops a computational pipeline for structure-based virtual screening in G-protein coupled receptors (GPCRs), a protein family targeted for countless disease indications. Inhibition of the protease-activated receptor 4 (PAR4) GPCR has demonstrated promise as a target in anti-platelet drug development. The goal of this screening effort is to obtain new chemistries for drug development that probes PAR4 deeper in the transmembrane region of the binding pocket, a feature critical for PAR4 inhibition. This pipeline uses an array of computational tools, including multiple-template comparative modeling in Rosetta, DOCK ultra-large screening libraries, Rosetta ligand docking and machine learning-based cheminformatics to prune new small-molecule chemistry. For broader impact, this protocol is general enough to be used across the GPCR super-family and potentially towards other protein targets for small molecule development.

The PhRMA Foundation provided me with the resources to jump-start my career as a scientist, while allowing me to become part of a larger community of world-class minds working towards improving human health. The PhRMA Foundation Informatics Fellowship gave me the unique opportunity to utilize my strengths in algorithm development to help us get one step closer towards achieving this goal.

Shannon Smith

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