6BQK

CRYSTAL STRUCTURE OF HEPATIS C VIRUS PROTEASE (NS3) COMPLEXED WITH TRIPEPTIDIC ACYL SULFONAMIDE INHIBITOR (COMPOUND 18)

Summary for 6BQK

• Entry DOI: 10.2210/pdb6bqk/pdb
• Descriptor: NS3 protease, N-(tert-butoxycarbonyl)-3-methyl-L-valyl-(4R)-4-[(7-chloro-4-methoxyisoquinolin-1-yl)oxy]-N-[(1R,2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2-(difluoromethyl)cyclopropyl]-L-prolinamide, ZINC ION, ... (4 entities in total)
• Functional Keywords: serine protease, viral protein, hydrolase
• Biological source: Hepatitis C virus
• Total number of polymer chains: 2
• Total formula weight: 48197.96

Authors

Klei, H.E.,Sack, J.S. (deposition date: 2017-11-28, release date: 2018-03-21, Last modification date: 2024-03-13)

Primary citation

Zheng, B.,D'Andrea, S.V.,Sun, L.Q.,Wang, A.X.,Chen, Y.,Hrnciar, P.,Friborg, J.,Falk, P.,Hernandez, D.,Yu, F.,Sheaffer, A.K.,Knipe, J.O.,Mosure, K.,Rajamani, R.,Good, A.C.,Kish, K.,Tredup, J.,Klei, H.E.,Paruchuri, M.,Ng, A.,Gao, Q.,Rampulla, R.A.,Mathur, A.,Meanwell, N.A.,McPhee, F.,Scola, P.M.
Potent Inhibitors of Hepatitis C Virus NS3 Protease: Employment of a Difluoromethyl Group as a Hydrogen-Bond Donor.
ACS Med Chem Lett, 9:143-148, 2018

PubMed Abstract: The design and synthesis of potent, tripeptidic acylsulfonamide inhibitors of HCV NS3 protease that contain a difluoromethyl cyclopropyl amino acid at P1 are described. A cocrystal structure of with a NS3/4A protease complex suggests the presence of a H-bond between the polarized C-H of the CHF moiety and the backbone carbonyl of Leu135 of the enzyme. Structure-activity relationship studies indicate that this H-bond enhances enzyme inhibitory potency by 13- and 17-fold compared to the CH and CF analogues, respectively, providing insight into the deployment of this unique amino acid.

PubMed: 29456803
DOI: 10.1021/acsmedchemlett.7b00503

Experimental method

X-RAY DIFFRACTION (1.97 Å)