3A2O

Crystal Structure of HIV-1 Protease Complexed with KNI-1689

3A2O の概要

• エントリーDOI: 10.2210/pdb3a2o/pdb
• 関連するPDBエントリー: 1hpx 1msm 1msn 2zye 3fx5
• 関連するBIRD辞書のPRD_ID: PRD_000584
• 分子名称: PROTEASE, GLYCEROL, (4R)-3-[(2S,3S)-3-{[(4-amino-2,6-dimethylphenoxy)acetyl]amino}-2-hydroxy-4-phenylbutanoyl]-5,5-dimethyl-N-(2-methylprop -2-en-1-yl)-1,3-thiazolidine-4-carboxamide, ... (4 entities in total)
• 機能のキーワード: hiv-1 protease, inhibitor, aspartyl protease, hydrolase, protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Human immunodeficiency virus 1
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 22142.17

構造登録者

Adachi, M.,Tamada, T.,Hidaka, K.,Kimura, T.,Kiso, Y.,Kuroki, R. (登録日: 2009-05-26, 公開日: 2010-03-02, 最終更新日: 2024-05-29)

主引用文献

Hidaka, K.,Kimura, T.,Abdel-Rahman, H.M.,Nguyen, J.T.,McDaniel, K.F.,Kohlbrenner, W.E.,Molla, A.,Adachi, M.,Tamada, T.,Kuroki, R.,Katsuki, N.,Tanaka, Y.,Matsumoto, H.,Wang, J.,Hayashi, Y.,Kempf, D.J.,Kiso, Y.
Small-sized human immunodeficiency virus type-1 protease inhibitors containing allophenylnorstatine to explore the S2' pocket.
J.Med.Chem., 52:7604-7617, 2009

PubMed Abstract: A series of HIV protease inhibitor based on the allophenylnorstatine structure with various P(2)' moieties were synthesized. Among these analogues, we discovered that a small allyl group would maintain potent enzyme inhibitory activity compared to the o-methylbenzyl moiety in clinical candidate 1 (KNI-764, also known as JE-2147, AG-1776, or SM-319777). Introduction of an anilinic amino group to 2 (KNI-727) improved water-solubility and anti-HIV-1 activity. X-ray crystallographic analysis of 13k (KNI-1689) with a beta-methallyl group at P(2)' position revealed hydrophobic interactions with Ala28, Ile84, and Ile50' similar to that of 1. The presence of an additional methyl group on the allyl group in compound 13k significantly increased anti-HIV activity over 1 while providing a rational drug design for structural minimization and improving membrane permeability.

PubMed: 19954246
DOI: 10.1021/jm9005115

実験手法

X-RAY DIFFRACTION (0.88 Å)