7LTN

Crystal structure of Mpro in complex with inhibitor CDD-1713

Summary for 7LTN

• Entry DOI: 10.2210/pdb7ltn/pdb
• Descriptor: 3C-like proteinase, 2-[4-(1~{H}-indazol-4-yl)-2-methanoyl-6-methoxy-phenoxy]-~{N},~{N}-dimethyl-ethanamide (3 entities in total)
• Functional Keywords: sars-cov-2 main protease, nanomolar potency inhibitor, dna-encoded library, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV,SARS-CoV-2)
• Total number of polymer chains: 1
• Total formula weight: 34178.92

Authors

Lu, S.,Palzkill, T.,Matzuk, M.,Young, D.,Melek, N.,Chamakuri, S. (deposition date: 2021-02-19, release date: 2021-11-10, Last modification date: 2024-11-20)

Primary citation

Chamakuri, S.,Lu, S.,Ucisik, M.N.,Bohren, K.M.,Chen, Y.C.,Du, H.C.,Faver, J.C.,Jimmidi, R.,Li, F.,Li, J.Y.,Nyshadham, P.,Palmer, S.S.,Pollet, J.,Qin, X.,Ronca, S.E.,Sankaran, B.,Sharma, K.L.,Tan, Z.,Versteeg, L.,Yu, Z.,Matzuk, M.M.,Palzkill, T.,Young, D.W.
DNA-encoded chemistry technology yields expedient access to SARS-CoV-2 M pro inhibitors.
Proc.Natl.Acad.Sci.USA, 118:-, 2021

PubMed Abstract: Severe 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) 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 [] = 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 ( = 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 ( = 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.

PubMed: 34426525
DOI: 10.1073/pnas.2111172118

Experimental method

X-RAY DIFFRACTION (1.79 Å)