1PRO

HIV-1 PROTEASE DIMER COMPLEXED WITH A-98881

1PRO の概要

• エントリーDOI: 10.2210/pdb1pro/pdb
• 分子名称: HIV-1 PROTEASE, (5R,6R)-2,4-BIS-(4-HYDROXY-3-METHOXYBENZYL)-1,5-DIBENZYL-3-OXO-6-HYDROXY-1,2,4-TRIAZACYCLOHEPTANE (3 entities in total)
• 機能のキーワード: aids, polyprotein, hydrolase, aspartic protease, endonuclease, rna-directed dna polymerase, hydrolase (aspartic protease)
• 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): P12499
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 22245.24

構造登録者

Park, C.H.,Kong, X.P.,Dealwis, C.G. (登録日: 1995-07-18, 公開日: 1996-08-17, 最終更新日: 2024-02-14)

主引用文献

Sham, H.L.,Zhao, C.,Stewart, K.D.,Betebenner, D.A.,Lin, S.,Park, C.H.,Kong, X.P.,Rosenbrook Jr., W.,Herrin, T.,Madigan, D.,Vasavanonda, S.,Lyons, N.,Molla, A.,Saldivar, A.,Marsh, K.C.,McDonald, E.,Wideburg, N.E.,Denissen, J.F.,Robins, T.,Kempf, D.J.,Plattner, J.J.,Norbeck, D.W.
A novel, picomolar inhibitor of human immunodeficiency virus type 1 protease.
J.Med.Chem., 39:392-397, 1996

PubMed Abstract: The design, synthesis, and molecular modeling studies of a novel series of azacyclic ureas, which are inhibitors of human immunodeficiency virus type 1 (HIV-1) protease that incorporate different ligands for the S1', S2, and S2' substrate-binding sites of HIV-1 protease are described. The synthesis of this series is highly flexible in the sense that the P1', P2, and P2' residues of the inhibitors can be changed independently. Molecular modeling studies on the phenyl ring of the P2 and P2' ligand suggested incorporation of hydrogen-bonding donor/acceptor groups at the 3' and 4-positions of the phenyl ring should increase binding potency. This led to the discovery of compound 7f (A-98881), which possesses high potency in the HIV-1 protease inhibition assay and the in vitro MT-4 cell culture assay (Ki = approximately 5 pM and EC50 = 0.002 microM). This compares well with the symmetrical cyclic urea 1 pioneered at DuPont Merck.

PubMed: 8558507
DOI: 10.1021/jm9507183

実験手法

X-RAY DIFFRACTION (1.8 Å)