7URB

Sars-Cov2 Main Protease in complex with CDD-1733

Summary for 7URB

• Entry DOI: 10.2210/pdb7urb/pdb
• Descriptor: 3C-like proteinase, (2P)-2-(isoquinolin-4-yl)-1-[(1s,3R)-3-(methylcarbamoyl)cyclobutyl]-N-{(1S)-1-[4-(trifluoromethyl)phenyl]butyl}-1H-benzimidazole-7-carboxamide (3 entities in total)
• Functional Keywords: sars-cov2, main protease, inhibitor, covalent, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 34482.24

Authors

Lu, S.,Palzkill, T.,Matzuk, M.M.,Judge, A. (deposition date: 2022-04-21, release date: 2023-07-26, Last modification date: 2023-08-16)

Primary citation

Jimmidi, R.,Chamakuri, S.,Lu, S.,Ucisik, M.N.,Chen, P.J.,Bohren, K.M.,Moghadasi, S.A.,Versteeg, L.,Nnabuife, C.,Li, J.Y.,Qin, X.,Chen, Y.C.,Faver, J.C.,Nyshadham, P.,Sharma, K.L.,Sankaran, B.,Judge, A.,Yu, Z.,Li, F.,Pollet, J.,Harris, R.S.,Matzuk, M.M.,Palzkill, T.,Young, D.W.
DNA-encoded chemical libraries yield non-covalent and non-peptidic SARS-CoV-2 main protease inhibitors.
Commun Chem, 6:164-164, 2023

PubMed Abstract: The development of SARS-CoV-2 main protease (M) inhibitors for the treatment of COVID-19 has mostly benefitted from X-ray structures and preexisting knowledge of inhibitors; however, an efficient method to generate M inhibitors, which circumvents such information would be advantageous. As an alternative approach, we show here that DNA-encoded chemistry technology (DEC-Tec) can be used to discover inhibitors of M. An affinity selection of a 4-billion-membered DNA-encoded chemical library (DECL) using M as bait produces novel non-covalent and non-peptide-based small molecule inhibitors of M with low nanomolar K values. Furthermore, these compounds demonstrate efficacy against mutant forms of M that have shown resistance to the standard-of-care drug nirmatrelvir. Overall, this work demonstrates that DEC-Tec can efficiently generate novel and potent inhibitors without preliminary chemical or structural information.

PubMed: 37542196
DOI: 10.1038/s42004-023-00961-y

Experimental method

X-RAY DIFFRACTION (2.14 Å)