7ltn | pdb_00007ltn
Crystal structure of Mpro in complex with inhibitor CDD-1713
Structural highlights
Publication Abstract from PubMedSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed more than 4 million humans globally, but there is no bona fide Food and Drug Administration-approved drug-like molecule to impede the COVID-19 pandemic. The sluggish pace of traditional therapeutic discovery is poorly suited to producing targeted treatments against rapidly evolving viruses. Here, we used an affinity-based screen of 4 billion DNA-encoded molecules en masse to identify a potent class of virus-specific inhibitors of the SARS-CoV-2 main protease (M(pro)) without extensive and time-consuming medicinal chemistry. CDD-1714, the initial three-building-block screening hit (molecular weight [MW] = 542.5 g/mol), was a potent inhibitor (inhibition constant [K i] = 20 nM). CDD-1713, a smaller two-building-block analog (MW = 353.3 g/mol) of CDD-1714, is a reversible covalent inhibitor of M(pro) (K i = 45 nM) that binds in the protease pocket, has specificity over human proteases, and shows in vitro efficacy in a SARS-CoV-2 infectivity model. Subsequently, key regions of CDD-1713 that were necessary for inhibitory activity were identified and a potent (K i = 37 nM), smaller (MW = 323.4 g/mol), and metabolically more stable analog (CDD-1976) was generated. Thus, screening of DNA-encoded chemical libraries can accelerate the discovery of efficacious drug-like inhibitors of emerging viral disease targets. DNA-encoded chemistry technology yields expedient access to SARS-CoV-2 M(pro) inhibitors.,Chamakuri S, Lu S, Ucisik MN, Bohren KM, Chen YC, Du HC, Faver JC, Jimmidi R, Li F, Li JY, Nyshadham P, Palmer SS, Pollet J, Qin X, Ronca SE, Sankaran B, Sharma KL, Tan Z, Versteeg L, Yu Z, Matzuk MM, Palzkill T, Young DW Proc Natl Acad Sci U S A. 2021 Sep 7;118(36). pii: 2111172118. doi:, 10.1073/pnas.2111172118. PMID:34426525[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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