Lunney E A, Hagen S E, Domagala J M, Humblet C, Kosinski J, Tait B D, Warmus J S, Wilson M, Ferguson D, Hupe D
Parke-Davis Pharmaceutical Research, Division of Warner Lambert, Ann Arbor, Michigan 48105-2430.
J Med Chem. 1994 Aug 19;37(17):2664-77. doi: 10.1021/jm00043a006.
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).
HIV-1蛋白酶已被确定为艾滋病研究中的一个重要靶标酶。虽然已经描述了许多肽衍生的抑制剂，但鉴定非肽抑制剂仍然是一个重要目标。使用HIV-1蛋白酶大规模筛选技术，4-羟基-3-(3-苯氧基丙基)-2H-1-苯并吡喃-2-酮(1)被鉴定为该酶的非肽竞争性抑制剂。采用基于蒙特卡罗的对接程序，将香豆素对接在酶的活性位点，揭示了一种结合模式，该模式后来通过X射线晶体分析得到证实。制备了几种类似物以测试结合相互作用并提高整体结合亲和力。该研究中活性最高的化合物是4,7-二羟基-3-[4-(2-甲氧基苯基)丁基]-2H-1-苯并吡喃-2-酮(31)。
