Abstract:

We have developed a three-dimensional pharmacophore model for the human immunodeficiency virus type I (HIV-1) integrase (IN) from diketoacids (DKAs) inhibitors using the genetic algorithm similarity program (GASP). For the selected training set, reliable drug-like properties and DKA-like pharmacophore features exist. Inhibitor conformations were mapped into the pharmacophore model and superimposed in their docking conformations. Corresponding positions between the pharmacophore model and IN residues were thus obtained. The pharmacophore model was refined according to whether the pharmacophore features were compatible with residues around them. Finally, an optimal pharmacophore model was generated and consisted of 1 hydrophobic feature, 3 hydrogen pair features and 1 hydrogen-bond donor feature. The pharmacophore model had higher reliability with a goodness of hit (GH) score of 0.56, a high percentage yield of actives (Y) of 63.6%and a lower false positive rate (FP) of 0.41%. This pharmacophore model can contribute to the discovery and design of new DKA-like inhibitors.

Key words: Human immunodeficiency virus, Integrase, Diketoacides, Inhibitor, Pharmacophore, Genetic algorithmsimilarity program