4DJO

Crystal Structure of wild-type HIV-1 Protease in Complex with MKP56

4DJO の概要

• エントリーDOI: 10.2210/pdb4djo/pdb
• 関連するPDBエントリー: 4DJP 4DJQ 4DJR
• 分子名称: Pol polyprotein, 2-[(dichloroacetyl)amino]ethyl [(2S,3R)-3-hydroxy-4-{[(4-methoxyphenyl)sulfonyl][(2S)-2-methylbutyl]amino}-1-phenylbutan-2-yl]carbamate, GLYCEROL, ... (6 entities in total)
• 機能のキーワード: hiv-1 protease, drug resistance, drug design, protease inhibitors, aids, aspartyl protease, 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: 22591.23

構造登録者

Schiffer, C.A.,Nalam, M.N.L. (登録日: 2012-02-02, 公開日: 2012-08-01, 最終更新日: 2024-02-28)

主引用文献

Parai, M.K.,Huggins, D.J.,Cao, H.,Nalam, M.N.,Ali, A.,Schiffer, C.A.,Tidor, B.,Rana, T.M.
Design, synthesis, and biological and structural evaluations of novel HIV-1 protease inhibitors to combat drug resistance.
J.Med.Chem., 55:6328-6341, 2012

PubMed Abstract: A series of new HIV-1 protease inhibitors (PIs) were designed using a general strategy that combines computational structure-based design with substrate-envelope constraints. The PIs incorporate various alcohol-derived P2 carbamates with acyclic and cyclic heteroatomic functionalities into the (R)-hydroxyethylamine isostere. Most of the new PIs show potent binding affinities against wild-type HIV-1 protease and three multidrug resistant (MDR) variants. In particular, inhibitors containing the 2,2-dichloroacetamide, pyrrolidinone, imidazolidinone, and oxazolidinone moieties at P2 are the most potent with K(i) values in the picomolar range. Several new PIs exhibit nanomolar antiviral potencies against patient-derived wild-type viruses from HIV-1 clades A, B, and C and two MDR variants. Crystal structure analyses of four potent inhibitors revealed that carbonyl groups of the new P2 moieties promote extensive hydrogen bond interactions with the invariant Asp29 residue of the protease. These structure-activity relationship findings can be utilized to design new PIs with enhanced enzyme inhibitory and antiviral potencies.

PubMed: 22708897
DOI: 10.1021/jm300238h

実験手法

X-RAY DIFFRACTION (1.78 Å)