Examining structural analogs of elvitegravir as potential inhibitors of HIV-1 integrase

Abstract

Acquired immunodeficiency syndrome (AIDS) is a major health problem in many parts of the world. The human immunodeficiency virus-1 integrase (HIV-1 IN) enzyme has been targeted in HIV patients for therapy. Several integrase inhibitors have been reported, but only elvitegravir (EVG), a new-generation drug, is clinically approved for HIV treatment. In the present work, we investigated two structural analogs of EVG as potential inhibitors of the target molecule, HIV-1 IN. The ligand binding site on HIV-1 IN was identified using Q-SiteFinder, and the HIV-1 IN protein was docked with ligand (EVG and/or analogs) using AutoDock 4. The results suggest that Lys173, Thr125, and His171 are involved in enzyme-substrate binding through hydrogen bonds. Single mutations carried out at Lys173, viz. Lys173Leu (polar > nonpolar) and Lys173Gln (polar > polar), in chain B using PyMOL showed the mutants to have lower binding energy when docked with analog 2, suggesting it to be more stable than analog 1. In conclusion, the mutant HIV-1 IN can bind EVG and its analogs. The physicochemical and pharmacokinetic parameters also show analog 2 to be a promising molecule that can be developed as an alternative to EVG to help overcome the problem of drug resistance by HIV to this inhibitor. Analog 2 may be used as an HIV-1 IN inhibitor with similar potential to that of EVG. Further validation through wet-lab studies, however, is required for future applications.

Evaluation of novel Saquinavir analogs for resistance mutation compatibility and potential as an HIV-Protease inhibitor drug

“…Saquinavir and the two designed analogs S1 with minimum and S2 with equal binding energy as that of Saquinavir were selected for pharmacokinetic studies as earlier [18] at ACD/I-lab [13] and the profile of the reference drug was collated to establish the practically desirable benchmark. The pharmacokinetic profile of the S1 and S2 molecules included absorption, distribution, metabolism, excretion (ADME) and toxicity, drug-like characteristics viz .…”

Development of HIV-1 integrase inhibitors: recent molecular modeling perspectives

“…In a docking experiment between LEDGINs and IN, a 20-Å radius active site was drawn on the original position of the LEDGF/ p75 integrase-binding domain (IBD) dipeptide Ile365-Asp366; a cavity was then automatically detected as the binding site [63]. Shah et al [58] used Q-Site Finder to predict favorable binding active sites on the IN surface. Tintori et al [62] presented an interesting approach to identify the binding sites: first, MD simulation was carried out to optimize the system and to detect the residues with a dominant role in IN dimer formation; then, an exploration with PocketPicker was utilized to identify possible binding pockets; finally, one binding pocket with a close proximity to these dominant residues was selected as a possible binding site for IN dimerization inhibitors.…”