8UTE

Structure of SARS-Cov2 3CLPro in complex with Compound 27

8UTE の概要

• エントリーDOI: 10.2210/pdb8ute/pdb
• 関連するPDBエントリー: 8UPS 8UPV 8UPW
• 分子名称: 3C-like proteinase nsp5, methyl {(2S)-1-[(1S,3aR,6aS)-1-{[(2R,3S)-6,6-difluoro-2-hydroxy-1-(methylamino)-1-oxoheptan-3-yl]carbamoyl}hexahydrocyclopenta[c]pyrrol-2(1H)-yl]-3,3-dimethyl-1-oxobutan-2-yl}carbamate, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: 3cl pro, mpro, inhibitor, viral protein, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34964.82

構造登録者

Krishnamurthy, H.,Zhuang, N.,Qiang, D.,Wu, Y.,Klein, D.J. (登録日: 2023-10-31, 公開日: 2024-03-06, 最終更新日: 2024-10-23)

主引用文献

Shurtleff, V.W.,Layton, M.E.,Parish, C.A.,Perkins, J.J.,Schreier, J.D.,Wang, Y.,Adam, G.C.,Alvarez, N.,Bahmanjah, S.,Bahnck-Teets, C.M.,Boyce, C.W.,Burlein, C.,Cabalu, T.D.,Campbell, B.T.,Carroll, S.S.,Chang, W.,de Lera Ruiz, M.,Dolgov, E.,Fay, J.F.,Fox, N.G.,Goh, S.L.,Hartingh, T.J.,Hurzy, D.M.,Kelly 3rd, M.J.,Klein, D.J.,Klingler, F.M.,Krishnamurthy, H.,Kudalkar, S.,Mayhood, T.W.,McKenna, P.M.,Murray, E.M.,Nahas, D.,Nawrat, C.C.,Park, S.,Qian, D.,Roecker, A.J.,Sharma, V.,Shipe, W.D.,Su, J.,Taggart, R.V.,Truong, Q.,Wu, Y.,Zhou, X.,Zhuang, N.,Perlin, D.S.,Olsen, D.B.,Howe, J.A.,McCauley, J.A.
Invention of MK-7845, a SARS-CoV-2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic.
J.Med.Chem., 67:3935-3958, 2024

PubMed Abstract: As SARS-CoV-2 continues to circulate, antiviral treatments are needed to complement vaccines. The virus's main protease, 3CLPro, is an attractive drug target in part because it recognizes a unique cleavage site, which features a glutamine residue at the P1 position and is not utilized by human proteases. Herein, we report the invention of MK-7845, a novel reversible covalent 3CLPro inhibitor. While most covalent inhibitors of SARS-CoV-2 3CLPro reported to date contain an amide as a Gln mimic at P1, MK-7845 bears a difluorobutyl substituent at this position. SAR analysis and X-ray crystallographic studies indicate that this group interacts with His163, the same residue that forms a hydrogen bond with the amide substituents typically found at P1. In addition to promising in vivo efficacy and an acceptable projected human dose with unboosted pharmacokinetics, MK-7845 exhibits favorable properties for both solubility and absorption that may be attributable to the unusual difluorobutyl substituent.

PubMed: 38365209
DOI: 10.1021/acs.jmedchem.3c02248

実験手法

X-RAY DIFFRACTION (1.45 Å)