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2000
Volume 20, Issue 8
  • ISSN: 1386-2073
  • E-ISSN: 1875-5402

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.

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/content/journals/cchts/10.2174/1386207320666170615104703
2017-09-01
2025-07-04
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