A NOVEL NONPEPTIDE HIV-1 PROTEASE INHIBITOR - ELUCIDATION OF THE BINDING MODE AND ITS APPLICATION IN THE DESIGN OF RELATED ANALOGS

被引：85

作者：

LUNNEY, EA ^{[1
]}

HAGEN, SE ^{[1
]}

DOMAGALA, JM ^{[1
]}

HUMBLET, C ^{[1
]}

KOSINSKI, J ^{[1
]}

TAIT, BD ^{[1
]}

WARMUS, JS ^{[1
]}

WILSON, M ^{[1
]}

FERGUSON, D ^{[1
]}

HUPE, D ^{[1
]}

TUMMINO, PJ ^{[1
]}

BALDWIN, ET ^{[1
]}

BHAT, TN ^{[1
]}

LIU, BS ^{[1
]}

ERICKSON, JW ^{[1
]}

机构：

[1] NCI,FREDERICK CANC RES & DEV CTR,PRI DYNCORP,STRUCT BIOCHEM PROGRAM,FREDERICK,MD 21702

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1994年 / 37卷 / 17期

关键词：

D O I：

10.1021/jm00043a006

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

HIV-1 protease has been identified as a significant target enzyme in AIDS research. While numerous peptide-derived inhibitors have been described, the identification of a nonpeptide inhibitor remains an important goal. Using an HIV-1 protease mass screening technique, 4-hydroxy-3-(3-phenoxypropyl)-2H-1-benzopyran-2-one (1) was identified as a nonpeptide competitive inhibitor of the enzyme. Employing a Monte Carlo-based docking procedure, the coumarin was docked in the active site of the enzyme, revealing a binding mode that was later confirmed by the X-ray crystal analysis, Several analogs were prepared to test the binding interactions and improve the overall binding affinity. The most active compound in the study was 4,7-dihydroxy-3-[4-(2-methoxyphenyl)butyl]-2H-1-benzopyran-2-one (31).

引用

页码：2664 / 2677

页数：14

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