Design of new HIV-1 protease inhibitors by pharmacophore searching

Four HIV - 1 protease inhibitors were hit by pharmacophore searching agains t a 3D structural database (containing 30, 000 newly reported compounds) de veloped by our group. By using conformation analysis we found that their fa vorable conformers contain the pharmacophore respectively. Additionally, al l 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 me thod integrated in the Spartan 5.0 program and found to be a little too sma ll. In order to meet the two principal factors: containing the pharmacophor e and having a moderate hydrophobic parameter, which were believed to be cr itical for an active HN - 1 protease inhibitor, some new structures were de signed by modifying the structures of these four compounds. These designed structures are simpler and believed easier to synthesize than the hitting c ompounds.