ABSTRACT
We report the results of the COVID Moonshot, a fully open-science, crowdsourced, and structure-enabled drug discovery campaign targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease. We discovered a noncovalent, nonpeptidic inhibitor scaffold with lead-like properties that is differentiated from current main protease inhibitors. Our approach leveraged crowdsourcing, machine learning, exascale molecular simulations, and high-throughput structural biology and chemistry. 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. All compound designs (>18,000 designs), crystallographic data (>490 ligand-bound x-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2400 compounds) for this campaign were shared rapidly and openly, creating a rich, open, and intellectual property-free knowledge base for future anticoronavirus drug discovery.
Subject(s)
COVID-19 Drug Treatment , Coronavirus 3C Proteases , Coronavirus Protease Inhibitors , Drug Discovery , SARS-CoV-2 , Humans , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/chemistry , Molecular Docking Simulation , Coronavirus Protease Inhibitors/chemical synthesis , Coronavirus Protease Inhibitors/chemistry , Coronavirus Protease Inhibitors/pharmacology , Structure-Activity Relationship , Crystallography, X-RayABSTRACT
An approach to the synthesis of 1-alkyl-5-((di)alkylamino)tetrazoles by nucleophilic substitution in 1-alkyl-5-sulfonyltetrazoles with anions generated from the primary or secondary amines was developed. Tolerance of the method to the presence of some functional groups (i.e., protected amine) in both components of the reaction was demonstrated. Obtained tetrazoles are promising building blocks for the design of peptide surrogates, in particular, for replacement approaches of alkyl urea derivatives.
Subject(s)
Peptides/chemistry , Tetrazoles/chemical synthesis , Amines/chemistry , Chemistry Techniques, Synthetic , Drug Design , Magnetic Resonance Spectroscopy , Molecular Structure , Sulfinic Acids/chemistry , Tetrazoles/chemistry , Urea/chemistryABSTRACT
The zwitterionic tetrahedral addition product 1 is the preferred form of the amino-aldehyde 4 in polar solvents and in the crystal, where a molecule of water controls the structure.
