关键词: 药效团, 构象, 蛋白酶, 抑制剂, 药物筛选, 计算机辅助设计

Four HIV-1 protease inhibitors were hit by pharmacophore searching against a 3D structural database (containing 30,000 newly reported compounds) developed by our group. By using conformation analysis we found that their favorable conformers contain the pharmacophore respectively. Additionally, all the four compounds have some common structural features such as an ortho-dihydroxyl substituted benzene ring with a carbonyl at para-position of the ring. Their hydrophobic parameters were calculated by Ghose-Crippen method integrated in the Spartan 5.0 program and found to be a little too small. In order to meet the two principal factors: containing the pharmacophore and having a moderate hydrophobic parameter, which were believed to be critical for an active HIV-1 protease inhibitor, some new structures were designed by modifying the structures of these four compounds. These designed structures are simpler and believed easier to synthesize than the hitting compounds.

Key words: CONFORMATION, PROTEASE, INHIBITOR, DRUG SCREENING, COMPUTER AIDED DESIGN