7LKT

1.50 A resolution structure of SARS-CoV-2 3CL protease in complex with inhibitor 2k

Summary for 7LKT

• Entry DOI: 10.2210/pdb7lkt/pdb
• Descriptor: 3C-like proteinase, (1S,2S)-2-((S)-2-(((adamantan-1-ylmethoxy)carbonyl)amino)-4-methylpentanamido)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propane-1-sulfonic acid, (1R,2S)-2-((S)-2-(((adamantan-1-ylmethoxy)carbonyl)amino)-4-methylpentanamido)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propane-1-sulfonic acid, ... (6 entities in total)
• Functional Keywords: covid-19, protease, severe acute respiratory syndrome coronavirus 2, sars-cov-2 3cl protease inhhibitors, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV)
• Total number of polymer chains: 2
• Total formula weight: 70889.85

Authors

Kashipathy, M.M.,Lovell, S.,Battaile, K.P.,Chamandi, S.D.,Rathnayake, A.D.,Nguyen, H.N.,Baird, M.A.,Kim, Y.,Shadipeni, N.,Chang, K.O.,Groutas, W.C. (deposition date: 2021-02-02, release date: 2021-02-17, Last modification date: 2024-11-13)

Primary citation

Dampalla, C.S.,Kim, Y.,Bickmeier, N.,Rathnayake, A.D.,Nguyen, H.N.,Zheng, J.,Kashipathy, M.M.,Baird, M.A.,Battaile, K.P.,Lovell, S.,Perlman, S.,Chang, K.O.,Groutas, W.C.
Structure-Guided Design of Conformationally Constrained Cyclohexane Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 3CL Protease.
J.Med.Chem., 64:10047-10058, 2021

PubMed Abstract: A series of nondeuterated and deuterated dipeptidyl aldehyde and masked aldehyde inhibitors that incorporate in their structure a conformationally constrained cyclohexane moiety was synthesized and found to potently inhibit severe acute respiratory syndrome coronavirus-2 3CL protease in biochemical and cell-based assays. Several of the inhibitors were also found to be nanomolar inhibitors of Middle East respiratory syndrome coronavirus 3CL protease. The corresponding latent aldehyde bisulfite adducts were found to be equipotent to the precursor aldehydes. High-resolution cocrystal structures confirmed the mechanism of action and illuminated the structural determinants involved in binding. The spatial disposition of the compounds disclosed herein provides an effective means of accessing new chemical space and optimizing pharmacological activity. The cellular permeability of the identified inhibitors and lack of cytotoxicity warrant their advancement as potential therapeutics for COVID-19.

PubMed: 34213885
DOI: 10.1021/acs.jmedchem.1c00319

Experimental method

X-RAY DIFFRACTION (1.5 Å)