5PZM

CRYSTAL STRUCTURE OF THE HEPATITIS C VIRUS NS5B RNA-DEPENDENT RNA POLYMERASE IN COMPLEX WITH 3-[2-(4-FLUOROPHENYL)-3-(METHYLCARBAMOYL)-1-BENZOFURAN-5-YL]BENZOIC ACID

5PZM の概要

• エントリーDOI: 10.2210/pdb5pzm/pdb
• Group deposition: NS5B 1b (G_1002026)
• 分子名称: RNA-directed RNA polymerase, (2E)-3-(4-{[(1-{[(13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-yl)carbonyl]amino}cyclopentyl)carbonyl]amino}phenyl)prop-2-enoic acid, SULFATE ION, ... (6 entities in total)
• 機能のキーワード: ns5b, polymerase, hcv, fingers, palm, thumb, transferase
• 由来する生物種: Hepatitis C virus genotype 1b (isolate Con1) (HCV)
• 細胞内の位置: Core protein p21: Host endoplasmic reticulum membrane ; Single-pass membrane protein . Core protein p19: Virion . Envelope glycoprotein E1: Virion membrane ; Single-pass type I membrane protein . Envelope glycoprotein E2: Virion membrane ; Single-pass type I membrane protein . p7: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Protease NS2-3: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Serine protease NS3: Host endoplasmic reticulum membrane ; Peripheral membrane protein . Non-structural protein 4A: Host endoplasmic reticulum membrane ; Single-pass type I membrane protein . Non-structural protein 4B: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Non-structural protein 5A: Host endoplasmic reticulum membrane ; Peripheral membrane protein . RNA-directed RNA polymerase: Host endoplasmic reticulum membrane ; Single-pass type I membrane protein : Q9WMX2
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 130626.60

構造登録者

Sheriff, S. (登録日: 2017-02-27, 公開日: 2017-05-10, 最終更新日: 2024-03-06)

主引用文献

Yeung, K.S.,Beno, B.R.,Parcella, K.,Bender, J.A.,Grant-Young, K.A.,Nickel, A.,Gunaga, P.,Anjanappa, P.,Bora, R.O.,Selvakumar, K.,Rigat, K.,Wang, Y.K.,Liu, M.,Lemm, J.,Mosure, K.,Sheriff, S.,Wan, C.,Witmer, M.,Kish, K.,Hanumegowda, U.,Zhuo, X.,Shu, Y.Z.,Parker, D.,Haskell, R.,Ng, A.,Gao, Q.,Colston, E.,Raybon, J.,Grasela, D.M.,Santone, K.,Gao, M.,Meanwell, N.A.,Sinz, M.,Soars, M.G.,Knipe, J.O.,Roberts, S.B.,Kadow, J.F.
Discovery of a Hepatitis C Virus NS5B Replicase Palm Site Allosteric Inhibitor (BMS-929075) Advanced to Phase 1 Clinical Studies.
J. Med. Chem., 60:4369-4385, 2017

PubMed Abstract: The hepatitis C virus (HCV) NS5B replicase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Inspired by the overlay of bound structures of three structurally distinct NS5B palm site allosteric inhibitors, the high-throughput screening hit anthranilic acid 4, the known benzofuran analogue 5, and the benzothiadiazine derivative 6, an optimization process utilizing the simple benzofuran template 7 as a starting point for a fragment growing approach was pursued. A delicate balance of molecular properties achieved via disciplined lipophilicity changes was essential to achieve both high affinity binding and a stringent targeted absorption, distribution, metabolism, and excretion profile. These efforts led to the discovery of BMS-929075 (37), which maintained ligand efficiency relative to early leads, demonstrated efficacy in a triple combination regimen in HCV replicon cells, and exhibited consistently high oral bioavailability and pharmacokinetic parameters across preclinical animal species. The human PK properties from the Phase I clinical studies of 37 were better than anticipated and suggest promising potential for QD administration.

PubMed: 28430437
DOI: 10.1021/acs.jmedchem.7b00328

実験手法

X-RAY DIFFRACTION (2.54 Å)