2HB3

Wild-type HIV-1 Protease in complex with potent inhibitor GRL06579

2HB3 の概要

• エントリーDOI: 10.2210/pdb2hb3/pdb
• 分子名称: Protease, CHLORIDE ION, SODIUM ION, ... (6 entities in total)
• 機能のキーワード: active-site cavity protease inhibitor catalytic aspartic acid, hydrolase
• 由来する生物種: Human immunodeficiency virus 1
• 細胞内の位置: Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): P03366
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 22286.49

構造登録者

Kovalevsky, A.Y.,Weber, I.T. (登録日: 2006-06-13, 公開日: 2006-08-29, 最終更新日: 2024-02-14)

主引用文献

Ghosh, A.K.,Sridhar, P.R.,Leshchenko, S.,Hussain, A.K.,Li, J.,Kovalevsky, A.Y.,Walters, D.E.,Wedekind, J.E.,Grum-Tokars, V.,Das, D.,Koh, Y.,Maeda, K.,Gatanaga, H.,Weber, I.T.,Mitsuya, H.
Structure-Based Design of Novel HIV-1 Protease Inhibitors To Combat Drug Resistance.
J.Med.Chem., 49:5252-5261, 2006

PubMed Abstract: Structure-based design and synthesis of novel HIV protease inhibitors are described. The inhibitors are designed specifically to interact with the backbone of HIV protease active site to combat drug resistance. Inhibitor 3 has exhibited exceedingly potent enzyme inhibitory and antiviral potency. Furthermore, this inhibitor maintains impressive potency against a wide spectrum of HIV including a variety of multi-PI-resistant clinical strains. The inhibitors incorporated a stereochemically defined 5-hexahydrocyclopenta[b]furanyl urethane as the P2-ligand into the (R)-(hydroxyethylamino)sulfonamide isostere. Optically active (3aS,5R,6aR)-5-hydroxy-hexahydrocyclopenta[b]furan was prepared by an enzymatic asymmetrization of meso-diacetate with acetyl cholinesterase, radical cyclization, and Lewis acid-catalyzed anomeric reduction as the key steps. A protein-ligand X-ray crystal structure of inhibitor 3-bound HIV-1 protease (1.35 A resolution) revealed extensive interactions in the HIV protease active site including strong hydrogen bonding interactions with the backbone. This design strategy may lead to novel inhibitors that can combat drug resistance.

PubMed: 16913714
DOI: 10.1021/jm060561m

実験手法

X-RAY DIFFRACTION (1.35 Å)