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A Blueprint for High Affinity SARS-CoV-2 Mpro Inhibitors from Activity-Based Compound Library Screening Guided by Analysis of Protein Dynamics

By January 30, 2024No Comments

The SARS-CoV-2 coronavirus outbreak continues to spread at a rapid rate worldwide. The main protease (Mpro) is an attractive target for anti-COVID-19 agents. Unexpected difficulties have been encountered in the design of specific inhibitors. Here, by analyzing an ensemble of ∼30 000 SARS-CoV-2 Mpro conformations from crystallographic studies and molecular simulations, we show that small structural variations in the binding site dramatically impact ligand binding properties. Hence, traditional druggability indices fail to adequately discriminate between highly and poorly druggable conformations of the binding site. By performing ∼200 virtual screenings of compound libraries on selected protein structures, we redefine the protein’s druggability as the consensus chemical space arising from the multiple conformations of the binding site formed upon ligand binding. Virtual screening studies were performed on a repurposing library including all the commercialized and under development drugs retrieved in the Clarivate Analytics Integrity database, merged with the internal chemical library from Dompè pharma company of already proven safe-in-man compounds and the Fraunhofer Institute BROAD Repurposing Library, removing duplicate structures. Known inhibitors of SARS-CoV Mpro were retrieved from several sources including the literature, the Clarivate Analytics Integrity database, the Excelra’s GOSTAR® database, and the data repository shared by the Global Health Drug Discovery Institute.