Molecular Docking and Molecular Dynamics Simulation Based Approach to Explore the Dual Inhibitor Against HIV-1 Reverse Transcriptase and Integrase

Abstract

Background: HIV integrase (IN) and reverse transcriptase (RT) are key enzymes for the replication of HIV-1. DNA polymerase and ribonuclease H (RNase H) are the two catalytic domains of HIV-1 RT which are validated as drug targets because of their essence for replication. IN and RNase H domain of RT shares striking structural similarity; it contains conserved DDE triad (two aspartates and one glutamate) and a pair of divalent Mg2+/Mn2+ ions at their catalytic core domain.

Objective: To search for novel compounds with dual inhibition of IN and RNase H for the drug development against both wild and drug-resistant strains of HIV.

Methods: In the present work, attempts have been made to search compounds against both IN and the RNase H domain of RT. Using structure-based virtual screening approach; Asinex database of small molecules was screened against the viral IN. Top thirty ranked hits obtained, were further evaluated against RNase H domain of RT using Extra Precision (XP) mode of Glide docking. Furthermore, eleven common potential hits were observed which were subjected to the in-silico prediction of drug-likeness properties. Later on, molecular dynamics simulation was performed for the best common active hit (AS6), in the complex with selected enzymes.

Result: In silico screening of Asinex database compounds against IN and RNase H resulted in total seven compounds namely AS3, AS5, AS6, AS15, AS17, AS18, and AS20 having dual inhibition activity.

Conclusion: This study warrants the dual inhibition activity of AS6 against IN and RNase H confirms its anti-HIV activity.

Keywords: Dual inhibitor; HIV-1; Integrase; Reverse transcriptase; molecular dynamics; virtual screening.