7VTH

The crystal structure of SARS-CoV-2 3CL protease in complex with compound 1

Summary for 7VTH

• Entry DOI: 10.2210/pdb7vth/pdb
• Descriptor: 3C-like proteinase, 2-[4-[[4-[bis(fluoranyl)methoxy]-2-methyl-phenyl]amino]-2,6-bis(oxidanylidene)-3-[[3,4,5-tris(fluoranyl)phenyl]methyl]-1,3,5-triazin-1-yl]-N-methyl-ethanamide (3 entities in total)
• Functional Keywords: viral protein-inhibitor complex, viral protein/inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• Total number of polymer chains: 2
• Total formula weight: 69845.46

Authors

Yamamoto, S.,Tachibana, Y. (deposition date: 2021-10-29, release date: 2022-04-06, Last modification date: 2023-11-29)

Primary citation

Unoh, Y.,Uehara, S.,Nakahara, K.,Nobori, H.,Yamatsu, Y.,Yamamoto, S.,Maruyama, Y.,Taoda, Y.,Kasamatsu, K.,Suto, T.,Kouki, K.,Nakahashi, A.,Kawashima, S.,Sanaki, T.,Toba, S.,Uemura, K.,Mizutare, T.,Ando, S.,Sasaki, M.,Orba, Y.,Sawa, H.,Sato, A.,Sato, T.,Kato, T.,Tachibana, Y.
Discovery of S-217622, a Noncovalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19.
J.Med.Chem., 65:6499-6512, 2022

PubMed Abstract: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and threatens public health and safety. Despite the rapid global spread of COVID-19 vaccines, effective oral antiviral drugs are urgently needed. Here, we describe the discovery of , the first oral noncovalent, nonpeptidic SARS-CoV-2 3CL protease inhibitor clinical candidate. was discovered via virtual screening followed by biological screening of an in-house compound library, and optimization of the hit compound using a structure-based drug design strategy. exhibited antiviral activity against current outbreaking SARS-CoV-2 variants and showed favorable pharmacokinetic profiles for once-daily oral dosing. Furthermore, dose-dependently inhibited intrapulmonary replication of SARS-CoV-2 in mice, indicating that this novel noncovalent inhibitor could be a potential oral agent for treating COVID-19.

PubMed: 35352927
DOI: 10.1021/acs.jmedchem.2c00117

Experimental method

X-RAY DIFFRACTION (2 Å)