In this study, researchers harnessed crowdsourcing and open science to develop new antivirals against SARS-CoV-2, focusing on its main protease, Mpro.
By Tarun Sai LomteNov 12 2023Reviewed by Susha Cheriyedath, M.Sc. A recent study published in the journal Science described a crowdsourced, open-science, and structure-enabled drug discovery program for the main protease of severe acute respiratory syndrome coronavirus 2 .
Crowdsourcing Drug Discovery: The COVID Moonshot Initiative In the present study, researchers reported open science discovery of potent antivirals for SARS-CoV-2. This program, "COVID Moonshot," was aimed at SARS-CoV-2 Mpro, building off rapid fragment screening that assessed unique fragment-soaked crystals and identified 71 hits populating the active site. The non-covalent fragment hits lacked inhibitory activity in an enzymatic assay but offered a high-resolution map of interactions.
A contract research organization , Enamine, was tasked with synthesizing compounds. The team computed synthetic routes of all submissions using the CRO's building block inventories and estimated synthetic complexity. The predicted synthetic complexity correlated with the actual time required for target compound synthesis. Next, alchemical free-energy calculations were used to estimate the potency of designs and analogs from virtual synthetic libraries.
Optimizing Antiviral Potency Through Structure-Activity Analysis Rapid structure-activity relationship evaluation was complemented by using nanomole-scale high-throughput chemistry , as exemplified by the optimizations of amide coupling to extend MAT-POS-4223bc15-21 and Chan-Lam reaction to extend ADA-UCB-6c2cb422-1. Seven and 20 compounds from the Chan-Lam and amide series, respectively, were selected for resynthesis.
By contrast, hydrophobic interactions with M165 and π-stacking interactions with H41 were predominant in P2. Next, the team explored P1, which has a steep SAR due to its preference for directional hydrogen-bond interactions and rigidity. Potency was increased by replacing pyridine with isoquinoline, introducing additional interactions with N142.
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