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

Author(s): Subhash Chander, Rajan Kumar Pandey, Ashok Penta, Bhanwar Singh Choudhary, Manish Sharma, Ruchi Malik, Vijay Kumar Prajapati*, Sankaranarayanan Murugesan*

Journal Name: Combinatorial Chemistry & High Throughput Screening
Accelerated Technologies for Biotechnology, Bioassays, Medicinal Chemistry and Natural Products Research

Volume 20 , Issue 8 , 2017

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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, virtual screening, molecular dynamics.

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Article Details

Year: 2017
Published on: 20 December, 2017
Page: [734 - 746]
Pages: 13
DOI: 10.2174/1386207320666170615104703
Price: $65

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