Publication
Open Science Discovery of Potent Non-Covalent SARS-CoV-2 Main Protease Inhibitors
Publisher:
Cold Spring Harbor Laboratory
Date:
30-10-2020
DOI:
10.1101/2020.10.29.339317
Abstract: The COVID-19 pandemic was a stark reminder that a barren global antiviral pipeline has grave humanitarian consequences. Pandemics could be prevented in principle by accessible, easily deployable broad-spectrum oral antivirals. Here we report the results of the COVID Moonshot , a fully open-science, crowd sourced, structure-enabled drug discovery c aign targeting the SARS-CoV-2 main protease. We discovered a novel chemical series that is differentiated from current Mpro inhibitors in that it maintains a new non-covalent, non-peptidic scaffold with nanomolar potency. Our approach leveraged crowdsourcing, high-throughput structural biology, machine learning, and exascale molecular simulations and high-throughput chemistry. In the process, we generated a detailed map of the structural plasticity of the SARS-CoV-2 main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. In a first for a structure-based drug discovery c aign, all compound designs ( ,000 designs), crystallographic data ( ligand-bound X-ray structures), assay data ( ,000 measurements), and synthesized molecules ( ,400 compounds) for this c aign were shared rapidly and openly, creating a rich open and IP-free knowledgebase for future anti-coronavirus drug discovery.