Rational in silico drug design of HIV-RT inhibitors through G-QSAR and molecular docking study of 4-arylthio and 4-aryloxy-3-iodopyridine-2(1-H)-one derivative

Abstract

Abstract Background Human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV). Antiretroviral therapy (ART) against HIV infection offers the promise of controlling disease progression and prolonging the survival of HIV-infected patients. Reverse transcriptase (RT) inhibitors remain the cornerstone of the drug regimen to treat AIDS. In this direction, by using group-based QSAR study (G-QSAR), identification of the structural need for the development of lead structure with reverse transcriptase inhibition on 97 reported structures was carried out. Docking analysis was performed further and suggested the structural properties required for binding affinity with the receptor. The molecules in the data set were fragmented into six (R1, R2, R3, R4, R5, and R6) by applying the fragmentation pattern. Three G-QSAR models were selected based on the statistical significance of the model. The molecular docking study was performed to explain the structural properties required for the design of potent HIV-RT inhibitors. Results The statistically validated QSAR models reveal the presence of higher hydrophobic groups containing single-bonded –Br atom, 2 aromatic bonded –NH group with less electronegativity, and entropic interaction fields at R2 essential for better anti-HIV activity. The presence of a lipophilic group at R3, oxygen and sulfur connected with two aromatic bonds at R4, and –CH3 group at R5 was fruitful for reverse transcriptase inhibition. Docking studies of the selected inhibitors with the active site of reverse transcriptase enzyme showed hydrogen bond, Van der Waal’s, charge, aromatic, and π–π interactions with residues present at the active site. Conclusion The results of the generated models provide significant site-specific insight into the structural requirements for reverse transcriptase inhibition during the design and development of novel anti-HIV compounds. Molecular docking study revealed the binding interaction between the ligand and the receptor which gave insight towards the structure-based design for the discovery of more potent compounds with better activity against HIV infection.