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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 and Sankaranarayanan Murugesan   Pages 1 - 13 ( 13 )

Abstract:


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 share the 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. Therefore, the search of compounds with dual inhibition of IN and RNase H can be the viable and more efficacious approach for the drug development against both wild and drug resistance strains of HIV. 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 studies were performed for the best common active hit (AS6), in the complex with selected proteins. Further, this study warrants the in vitro study for the experimental validation of AS6 mediated dual inhibition of aforementioned targets to confirm its anti-HIV activity.

Keywords:

Dual inhibitor, HIV-1, Integrase, Reverse transcriptase, Virtual screening

Affiliation:

Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science, Pilani-333031, Rajasthan, Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Kishangarh-305817 Rajasthan, Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science, Pilani-333031, Rajasthan, Department of Pharmacy, School of Chemical Sciences, Central University of Rajasthan, Kishangarh-305817, Ajmer, Rajasthan, College of Pharmacy, Maharishi Markendeshwar University, Mullana, Ambala, Haryana, Department of Pharmacy, School of Chemical Sciences, Central University of Rajasthan, Kishangarh-305817, Ajmer, Rajasthan, Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Kishangarh-305817 Rajasthan, Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science, Pilani-333031, Rajasthan



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