4K8B

Crystal structure of HCV NS3/4A protease complexed with inhibitor

4K8B の概要

• エントリーDOI: 10.2210/pdb4k8b/pdb
• 関連するBIRD辞書のPRD_ID: PRD_001064
• 分子名称: NS3 protease, Nonstructural protein, ZINC ION, ... (6 entities in total)
• 機能のキーワード: protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Hepatitis C virus; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 42407.13

構造登録者

Nar, H. (登録日: 2013-04-18, 公開日: 2014-03-26, 最終更新日: 2023-11-08)

主引用文献

Laplante, S.R.,Nar, H.,Lemke, C.T.,Jakalian, A.,Aubry, N.,Kawai, S.H.
Ligand bioactive conformation plays a critical role in the design of drugs that target the hepatitis C virus NS3 protease.
J.Med.Chem., 57:1777-1789, 2014

PubMed Abstract: A ligand-focused strategy employed NMR, X-ray, modeling, and medicinal chemistry to expose the critical role that bioactive conformation played in the design of a variety of drugs that target the HCV protease. The bioactive conformation (bound states) were determined for key inhibitors identified along our drug discovery pathway from the hit to clinical compounds. All adopt similar bioactive conformations for the common core derived from the hit peptide DDIVPC. A carefully designed SAR analysis, based on the advanced inhibitor 1 in which the P1 to P3 side chains and the N-terminal Boc were sequentially truncated, revealed a correlation between affinity and the relative predominance of the bioactive conformation in the free state. Interestingly, synergistic conformation effects on potency were also noted. Comparisons with clinical and recently marketed drugs from the pharmaceutical industry showed that all have the same core and similar bioactive conformations. This suggested that the variety of appendages discovered for these compounds also properly satisfy the bioactive conformation requirements and allowed for a large variety of HCV protease drug candidates to be designed.

PubMed: 24144444
DOI: 10.1021/jm401338c

実験手法

X-RAY DIFFRACTION (2.8 Å)