Pharmacophore modelling and electronic feature analysis of hydroxamic acid derivatives, the HIV integrase inhibitors

Abstract

Hydroxamic acid derivatives with metal ion binding properties were collected from the literature to generate a pharmacophore and 3D-QSAR model for HIV strand transfer inhibition. The derived pharmacophore model (AAAHRR) recognizes both metal ion binding site and hydrophobic group. The QSAR model generated using this hypothesis expressed statistical significance (r 2 = 0.971 for the training set and q 2 = 0.913 for the test set). The ability of this pharmacophore model to retrieve other metal ion binding inhibitors was examined by screening the ChemBank database (ligandinfo) incorporated with 10 known strand transfer inhibitors. The studied favourable and unfavourable contours of chemical features (H-bond donor, acceptor and hydrophobic sites) revealed the role of hydrophobic substitution at the fluorobenzene ring and cyclization of the metal ion binding hydroxamic acid in effective integrase inhibition. Analysis of the frontier orbitals, HOMO and LUMO revealed that the nucleophilic / electrophilic interactions depend on the significant overlapping observed at the azaindole and hydroxamic acid groups. In essence, the generated pharmacophore model is competent enough to disclose the essential site-specific interactions involved in the inhibition of HIV integrase, and hence can be used in virtual screening to identify novel scaffolds as leads with increased anti-viral potency.