6PJO

HIV-1 Protease NL4-3 WT in Complex with LR2-42

6PJO の概要

• エントリーDOI: 10.2210/pdb6pjo/pdb
• 分子名称: Protease NL4-3, methyl [(1S)-1-cyclopentyl-2-({(2S,4S,5S)-5-[({[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy}carbonyl)amino]-4-hydroxy-1,6-diphenylhexan-2-yl}amino)-2-oxoethyl]carbamate, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: hiv, nl4-3 protease, drug resistance, protease inhibitor, hydrolase inhibitor complex, hydrolase, 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: 22383.47

構造登録者

Lockbaum, G.J.,Rusere, L.N.,Henes, M.,Kosovrasti, K.,Lee, S.K.,Spielvogel, E.,Nalivaika, E.A.,Swanstrom, R.,KurtYilmaz, N.,Schiffer, C.A.,Ali, A. (登録日: 2019-06-28, 公開日: 2020-07-01, 最終更新日: 2024-03-13)

主引用文献

Rusere, L.N.,Lockbaum, G.J.,Henes, M.,Lee, S.K.,Spielvogel, E.,Rao, D.N.,Kosovrasti, K.,Nalivaika, E.A.,Swanstrom, R.,Kurt Yilmaz, N.,Schiffer, C.A.,Ali, A.
Structural Analysis of Potent Hybrid HIV-1 Protease Inhibitors Containing Bis-tetrahydrofuran in a Pseudosymmetric Dipeptide Isostere.
J.Med.Chem., 63:8296-8313, 2020

PubMed Abstract: The design, synthesis, and X-ray structural analysis of hybrid HIV-1 protease inhibitors (PIs) containing bis-tetrahydrofuran (bis-THF) in a pseudo-C-symmetric dipeptide isostere are described. A series of PIs were synthesized by incorporating bis-THF of darunavir on either side of the Phe-Phe isostere of lopinavir in combination with hydrophobic amino acids on the opposite P2/P2' position. Structure-activity relationship studies indicated that the bis-THF moiety can be attached at either the P2 or P2' position without significantly affecting potency. However, the group on the opposite P2/P2' position had a dramatic effect on potency depending on the size and shape of the side chain. Cocrystal structures of inhibitors with wild-type HIV-1 protease revealed that the bis-THF moiety retained similar interactions as observed in the darunavir-protease complex regardless of the position on the Phe-Phe isostere. Analyses of cocrystal structures and molecular dynamics simulations provide insights into optimizing HIV-1 PIs containing bis-THF in non-sulfonamide dipeptide isosteres.

PubMed: 32672965
DOI: 10.1021/acs.jmedchem.0c00529

実験手法

X-RAY DIFFRACTION (1.95 Å)