7N44

Crystal structure of the SARS-CoV-2 (2019-NCoV) main protease in complex with 5-(3-{3-chloro-5-[(5-methyl-1,3-thiazol-4-yl)methoxy]phenyl}-2-oxo-2H-[1,3'-bipyridin]-5-yl)pyrimidine-2,4(1H,3H)-dione (compound 13)

7N44 の概要

• エントリーDOI: 10.2210/pdb7n44/pdb
• 分子名称: 3C-like proteinase, 5-(3-{3-chloro-5-[(5-methyl-1,3-thiazol-4-yl)methoxy]phenyl}-2-oxo-2H-[1,3'-bipyridin]-5-yl)pyrimidine-2,4(1H,3H)-dione (3 entities in total)
• 機能のキーワード: novel coronavirus, antiviral, drug design, viral protein, hydrolase
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34345.51

構造登録者

Reilly, R.A.,Zhang, C.H.,Deshmukh, M.G.,Ippolito, J.A.,Hollander, K.,Jorgensen, W.L.,Anderson, K.S. (登録日: 2021-06-03, 公開日: 2021-07-21, 最終更新日: 2023-10-18)

主引用文献

Zhang, C.H.,Spasov, K.A.,Reilly, R.A.,Hollander, K.,Stone, E.A.,Ippolito, J.A.,Liosi, M.E.,Deshmukh, M.G.,Tirado-Rives, J.,Zhang, S.,Liang, Z.,Miller, S.J.,Isaacs, F.,Lindenbach, B.D.,Anderson, K.S.,Jorgensen, W.L.
Optimization of Triarylpyridinone Inhibitors of the Main Protease of SARS-CoV-2 to Low-Nanomolar Antiviral Potency.
Acs Med.Chem.Lett., 12:1325-1332, 2021

PubMed Abstract: Non-covalent inhibitors of the main protease (M) of SARS-CoV-2 having a pyridinone core were previously reported with IC values as low as 0.018 μM for inhibition of enzymatic activity and EC values as low as 0.8 μM for inhibition of viral replication in Vero E6 cells. The series has now been further advanced by consideration of placement of substituted five-membered-ring heterocycles in the S4 pocket of M and N-methylation of a uracil ring. Free energy perturbation calculations provided guidance on the choice of the heterocycles, and protein crystallography confirmed the desired S4 placement. Here we report inhibitors with EC values as low as 0.080 μM, while remdesivir yields values of 0.5-2 μM in side-by-side testing with infectious SARS-CoV-2. A key factor in the improvement is enhanced cell permeability, as reflected in PAMPA measurements. Compounds and are particularly promising as potential therapies for COVID-19, featuring IC values of 0.044-0.061 μM, EC values of ca. 0.1 μM, good aqueous solubility, and no cytotoxicity.

PubMed: 34408808
DOI: 10.1021/acsmedchemlett.1c00326

実験手法

X-RAY DIFFRACTION (1.94 Å)