4COE

Macrocyclic Transition-State Mimicking HIV-1 Protease Inhibitors Encompassing a Tertiary Alcohol

4COE の概要

• エントリーDOI: 10.2210/pdb4coe/pdb
• 関連するPDBエントリー: 4CP7
• 分子名称: PROTEASE, CHLORIDE ION, methyl {(2S)-1-[2-(biphenyl-4-ylmethyl)-2-{(4R)-4-hydroxy-5-{[(2S)-3-methyl-1-oxo-1-(prop-2-en-1-ylamino)butan-2-yl]amino}-5-oxo-4-[4-(prop-2-en-1-yl)benzyl]pentyl}hydrazinyl]-3,3-dimethyl-1-oxobutan-2-yl}carbamate, ... (4 entities in total)
• 機能のキーワード: hydrolase, inhibitor, rational drug design, enzyme
• 由来する生物種: HUMAN IMMUNODEFICIENCY VIRUS
• 細胞内の位置: Gag-Pol polyprotein: Host cell membrane; Lipid-anchor. Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P03366
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 22411.65

構造登録者

DeRosa, M.,Unge, J.,Motwani, H.V.,Rosenquist, A.,Vrang, L.,Wallberg, H.,Larhed, M. (登録日: 2014-01-28, 公開日: 2014-12-10, 最終更新日: 2024-05-01)

主引用文献

De Rosa, M.,Unge, J.,Motwani, H.V.,Rosenquist, A.,Vrang, L.,Wallberg, H.,Larhed, M.
Synthesis of P1'-Functionalized Macrocyclic Transition-State Mimicking HIV-1 Protease Inhibitors Encompassing a Tertiary Alcohol.
J.Med.Chem., 57:6444-, 2014

PubMed Abstract: Seven novel tertiary alcohol containing linear HIV-1 protease inhibitors (PIs), decorated at the para position of the benzyl group in the P1' side with (hetero)aromatic moieties, were synthesized and biologically evaluated. To study the inhibition and antiviral activity effect of P1-P3 macrocyclization, 14- and 15-membered macrocyclic PIs were prepared by ring-closing metathesis of the corresponding linear PIs. The macrocycles were more active than the linear precursors and compound 10f, with a 2-thiazolyl group in the P1' position, was the most potent PI of this new series (Ki 2.2 nM, EC50 0.2 μM). Co-crystallized complexes of both linear and macrocyclic PIs with the HIV-1 protease enzyme were prepared and analyzed.

PubMed: 25054811
DOI: 10.1021/JM500434Q

実験手法

X-RAY DIFFRACTION (2.45 Å)