2XWY

Structure of MK-3281, a Potent Non-Nucleoside Finger-Loop Inhibitor, in complex with the Hepatitis C Virus NS5B Polymerase

Summary for 2XWY

• Entry DOI: 10.2210/pdb2xwy/pdb
• Related: 1A1Q 1BT7 1C2P 1CSJ 1CU1 1GX5 1GX6 1JXP 1NHU 1NHV 1NS3 1OS5 1QUV 2AWZ 2AX0 2AX1 2BRK 2BRL 2I1R 2JC0 2JC1 2WCX 2WHO 8OHM
• Descriptor: RNA-DIRECTED RNA POLYMERASE, (7R)-14-cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl)amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid, MANGANESE (II) ION, ... (4 entities in total)
• Functional Keywords: transferase, allosteric inhibitor, nucleotidyltransferase
• Biological source: HEPATITIS C VIRUS
• Total number of polymer chains: 1
• Total formula weight: 60358.21

Authors

Di Marco, S.,Baiocco, P. (deposition date: 2010-11-06, release date: 2010-12-22, Last modification date: 2023-12-20)

Primary citation

Narjes, F.,Crescenzi, B.,Ferrara, M.,Habermann, J.,Colarusso, S.,Del Rosario Rico Ferreira, M.,Stansfield, I.,Mackay, A.C.,Conte, I.,Ercolani, C.,Zaramella, S.,Palumbi, M.C.,Meuleman, P.,Leroux-Roels, G.,Giuliano, C.,Fiore, F.,Di Marco, S.,Baiocco, P.,Koch, U.,Migliaccio, G.,Altamura, S.,Laufer, R.,De Francesco, R.,Rowley, M.
Discovery of (7R)-14-Cyclohexyl-7-{[2-(Dimethylamino)Ethyl] (Methyl)Amino}-7,8-Dihydro-6H-Indolo[1,2-E][1,5] Benzoxazocine -11-Carboxylic Acid (Mk-3281), a Potent and Orally Bioavailable Finger-Loop Inhibitor of the Hepatitis C Virus Ns5B Polymerase
J.Med.Chem., 54:289-, 2011

PubMed Abstract: Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral genome and has been a prime target for drug discovery efforts. Here, we report on the further development of tetracyclic indole inhibitors, binding to an allosteric site on the thumb domain. Structure-activity relationship (SAR) studies around an indolo-benzoxazocine scaffold led to the identification of compound 33 (MK-3281), an inhibitor with good potency in the HCV subgenomic replication assay and attractive molecular properties suitable for a clinical candidate. The compound caused a consistent decrease in viremia in vivo using the chimeric mouse model of HCV infection.

PubMed: 21141896
DOI: 10.1021/JM1013105

Experimental method

X-RAY DIFFRACTION (2.53 Å)