4NWL

Crystal structure of hepatis c virus protease (ns3) complexed with bms-650032 aka n-(tert-butoxycarbonyl)-3-me thyl-l-valyl-(4r)-4-((7-chloro-4-methoxy-1-isoquinolinyl)o xy)-n-((1r,2s)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylc yclopropyl)-l-prolinamide

Summary for 4NWL

• Entry DOI: 10.2210/pdb4nwl/pdb
• Related: 4NWK
• Descriptor: HCV NS3 1a Protease, N-(tert-butoxycarbonyl)-3-methyl-L-valyl-(4R)-4-[(7-chloro-4-methoxyisoquinolin-1-yl)oxy]-N-{(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-L-prolinamide, ZINC ION, ... (4 entities in total)
• Functional Keywords: hydrolase/hydrolase inhibitor, serine protease, hydrolase-hydrolase inhibitor complex
• Biological source: Hepatitis C virus; More
• Cellular location: Virion : A8DG50
• Total number of polymer chains: 2
• Total formula weight: 48150.02

Authors

Muckelbauer, J.K.,Klei, H.E. (deposition date: 2013-12-06, release date: 2014-03-26, Last modification date: 2024-02-28)

Primary citation

Scola, P.M.,Wang, A.X.,Good, A.C.,Sun, L.Q.,Combrink, K.D.,Campbell, J.A.,Chen, J.,Tu, Y.,Sin, N.,Venables, B.L.,Sit, S.Y.,Chen, Y.,Cocuzza, A.,Bilder, D.M.,D'Andrea, S.,Zheng, B.,Hewawasam, P.,Ding, M.,Thuring, J.,Li, J.,Hernandez, D.,Yu, F.,Falk, P.,Zhai, G.,Sheaffer, A.K.,Chen, C.,Lee, M.S.,Barry, D.,Knipe, J.O.,Li, W.,Han, Y.H.,Jenkins, S.,Gesenberg, C.,Gao, Q.,Sinz, M.W.,Santone, K.S.,Zvyaga, T.,Rajamani, R.,Klei, H.E.,Colonno, R.J.,Grasela, D.M.,Hughes, E.,Chien, C.,Adams, S.,Levesque, P.C.,Li, D.,Zhu, J.,Meanwell, N.A.,McPhee, F.
Discovery and Early Clinical Evaluation of BMS-605339, a Potent and Orally Efficacious Tripeptidic Acylsulfonamide NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection.
J.Med.Chem., 57:1708-1729, 2014

PubMed Abstract: The discovery of BMS-605339 (35), a tripeptidic inhibitor of the NS3/4A enzyme, is described. This compound incorporates a cyclopropylacylsulfonamide moiety that was designed to improve the potency of carboxylic acid prototypes through the introduction of favorable nonbonding interactions within the S1' site of the protease. The identification of 35 was enabled through the optimization and balance of critical properties including potency and pharmacokinetics (PK). This was achieved through modulation of the P2* subsite of the inhibitor which identified the isoquinoline ring system as a key template for improving PK properties with further optimization achieved through functionalization. A methoxy moiety at the C6 position of this isoquinoline ring system proved to be optimal with respect to potency and PK, thus providing the clinical compound 35 which demonstrated antiviral activity in HCV-infected patients.

PubMed: 24555570
DOI: 10.1021/jm401840s

Experimental method

X-RAY DIFFRACTION (2.2 Å)