2I0D

Crystal structure of AD-81 complexed with wild type HIV-1 protease

2I0D の概要

• エントリーDOI: 10.2210/pdb2i0d/pdb
• 関連するPDBエントリー: 2IOA
• 分子名称: Protease, PHOSPHATE ION, (5S)-3-(3-ACETYLPHENYL)-N-[(1S,2R)-1-BENZYL-2-HYDROXY-3-{ISOBUTYL[(4-METHOXYPHENYL)SULFONYL]AMINO}PROPYL]-2-OXO-1,3-OXAZOLIDINE-5-CARBOXAMIDE, ... (5 entities in total)
• 機能のキーワード: drug design, hiv-1 protease, protease inhibitors, hydrolase
• 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: 22708.25

構造登録者

Nalam, M.N.L.,Schiffer, C.A.,Ali, A.,Reddy, K.K.,Cao, H.,Anjum, S.G.,Rana, T.M. (登録日: 2006-08-10, 公開日: 2006-12-19, 最終更新日: 2023-08-30)

主引用文献

Ali, A.,Reddy, G.S.,Cao, H.,Anjum, S.G.,Nalam, M.N.,Schiffer, C.A.,Rana, T.M.
Discovery of HIV-1 Protease Inhibitors with Picomolar Affinities Incorporating N-Aryl-oxazolidinone-5-carboxamides as Novel P2 Ligands.
J.Med.Chem., 49:7342-7356, 2006

PubMed Abstract: Here, we describe the design, synthesis, and biological evaluation of novel HIV-1 protease inhibitors incorporating N-phenyloxazolidinone-5-carboxamides into the (hydroxyethylamino)sulfonamide scaffold as P2 ligands. Series of inhibitors with variations at the P2 phenyloxazolidinone and the P2' phenylsulfonamide moieties were synthesized. Compounds with the (S)-enantiomer of substituted phenyloxazolidinones at P2 show highly potent inhibitory activities against HIV-1 protease. The inhibitors possessing 3-acetyl, 4-acetyl, and 3-trifluoromethyl groups at the phenyl ring of the oxazolidinone fragment are the most potent in each series, with K(i) values in the low picomolar (pM) range. The electron-donating groups 4-methoxy and 1,3-dioxolane are preferred at P2' phenyl ring, as compounds with other substitutions show lower binding affinities. Attempts to replace the isobutyl group at P1' with small cyclic moieties caused significant loss of affinities in the resulting compounds. Crystal structure analysis of the two most potent inhibitors in complex with the HIV-1 protease provided valuable information on the interactions between the inhibitor and the protease enzyme. In both inhibitor - enzyme complexes, the carbonyl group of the oxazolidinone ring makes hydrogenbond interactions with relatively conserved Asp29 residue of the protease. Potent inhibitors from each series incorporating various phenyloxazolidinone based P2 ligands were selected and their activities against a panel of multidrug-resistant (MDR) protease variants were determined. Interestingly, the most potent protease inhibitor starts out with extremely tight affinity for the wild-type enzyme (K(i) = 0.8 pM), and even against the MDR variants it retains picomolar to low nanomolar K(i), which is highly comparable with the best FDA-approved protease inhibitors.

PubMed: 17149864
DOI: 10.1021/jm060666p

実験手法

X-RAY DIFFRACTION (1.95 Å)