5JFU

HIV-1 wild Type protease with GRL-007-14A (a Adamantane P1-Ligand with bis-THF in P2 and benzylamine in P1')

5JFU の概要

• エントリーDOI: 10.2210/pdb5jfu/pdb
• 関連するPDBエントリー: 2IEN 5JFP 5JG1
• 分子名称: Protease, CHLORIDE ION, (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(2S,3R)-4-{benzyl[(4-methoxyphenyl)sulfonyl]amino}-3-hydroxy-1-[(3R,5R,7R)-tricyclo[3.3.1.1~3,7~]decan-1-yl]butan-2-yl}carbamate, ... (4 entities in total)
• 機能のキーワード: adamantane, hiv-1 protease inhibitor grl-007-14a, darunavir, multidrug-resistant, 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: 22207.07

構造登録者

Wang, Y.-F.,Agniswamy, J.,Weber, I.T. (登録日: 2016-04-19, 公開日: 2016-09-21, 最終更新日: 2023-09-27)

主引用文献

Ghosh, A.K.,Osswald, H.L.,Glauninger, K.,Agniswamy, J.,Wang, Y.F.,Hayashi, H.,Aoki, M.,Weber, I.T.,Mitsuya, H.
Probing Lipophilic Adamantyl Group as the P1-Ligand for HIV-1 Protease Inhibitors: Design, Synthesis, Protein X-ray Structural Studies, and Biological Evaluation.
J.Med.Chem., 59:6826-6837, 2016

PubMed Abstract: A series of potent HIV-1 protease inhibitors with a lipophilic adamantyl P1 ligand have been designed, synthesized, and evaluated. We have developed an enantioselective synthesis of adamantane-derived hydroxyethylamine isosteres utilizing Sharpless asymmetric epoxidation as the key step. Various inhibitors incorporating P1-adamantylmethyl in combination with P2 ligands such as 3-(R)-THF, 3-(S)-THF, bis-THF, and THF-THP were examined. The S1' pocket was also probed with phenyl and phenylmethyl ligands. Inhibitor 15d, with an isobutyl P1' ligand and a bis-THF P2 ligand, proved to be the most potent of the series. The cLogP value of inhibitor 15d is improved compared to inhibitor 2 with a phenylmethyl P1-ligand. X-ray structural studies of 15d, 15h, and 15i with HIV-1 protease complexes revealed molecular insight into the inhibitor-protein interaction.

PubMed: 27389367
DOI: 10.1021/acs.jmedchem.6b00639

実験手法

X-RAY DIFFRACTION (1.7 Å)