John Chodera of the Sloan Kettering Institute for Cancer Research is supported by an award from the Chemical Theory, Models and Computational Methods program in the Division of Chemistry to identify the biophysical determinants of inhibition for the SARS-CoV-2 main viral protease (Mpro). Mpro is an essential enzyme in the virus that causes COVID-19. The Chodera lab develops physical models accelerated by inexpensive consumer-grade graphics processing units (GPUs) to predict which small molecules might bind and inhibit disease-relevant proteins. The Chodera lab is part of the Folding@home Consortium, a research collaboration that uses the Folding@home distributed computing environment to run these calculations. This computing resource is donated by a network of volunteers around the world. Recently, in response to the COVID-19 pandemic, Folding@home became the largest computing platform of any kind in the world, with >25M CPU cores and >600K GPUs participating at any given time. The Chodera lab will use Folding@home to integrate computation and experiment to rapidly identify high-affinity inhibitors of Mpro and to elucidate key interactions required for effective inhibition. They work with collaborators at Informatics Matters (a team that works to enumerates synthetically feasible compounds), Enamine (to synthesize compounds), the Diamond Light Source (to crystallize chemical compounds), the London lab at the Weizmann (to assay compounds), and PostEra (to make the results rapidly and publicly available in a manner that can accelerate research on Mpro inhibition in other research laboratories and pharmaceutical companies).
Over the last two months, Folding@home has become the world’s largest computing resource (>2.5 exaflops, >25M CPU cores, >600K GPUs) in service of COVID-19 specific research. John Chodera, a founding investigator in the Folding@home Consortium, and collaborators have established a rapid pipeline to go from the selection of molecules within the 14B compound Enamine REAL Space virtual synthetic library to key biophysical data (X-ray structures and affinities) to SARS-CoV-2 main viral protease (Mpro) with ~2 week turnaround time. His laboratory is now using relative alchemical free energy methods to assess strategies for rapidly progressing an initial set of 68 small molecule X-ray structures from an initial screen for weak inhibitors toward high-affinity ligands. The team also identifies key biophysical determinants of high-affinity ligand binding within the active site of Mpro, and benchmark the propsective accuracy of small molecule force fields to inform the development of next-generation force fields. The laboratory is selecting molecules from Enamine REAL Space to be synthesized, soaked to produce X-ray structures by DiamondMX/XChem, and assayed for Mpro inhibition by the London lab at the Weizmann Institute via collaborations already in place. All computational data is being rapidly disseminated online via the NSF-funded Molecular Sciences Software Institute (MolSSI) COVID-19 Molecular Structures and Therapeutics Hub and the open science COVID Moonshot program to maximize multiple downstream uses for fundamental research and the opportunity for broader impacts in applied and translational areas.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
