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

Debadash Panigrahi,Susanta Kumar Sahu,Amiyakanta Mishra

doi:10.1186/s43088-020-00075-7

Debadash Panigrahi, Susanta Kumar Sahu + Show 1 more

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https://doi.org/10.1186/s43088-020-00075-7

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Abstract

BackgroundHuman 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.ResultsThe 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.ConclusionThe 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.

Highlights

Human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/acquired immunodeficiency syndrome (AIDS)) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV)
The whole data set of compounds were divided into training and test sets, and three group-based quantitative structure-activity relationship (QSAR) study (G-QSAR) models were developed by a simulated annealing algorithm (SA) coupled with multiple linear regression (MLR), partial least squares regression (PLS), and principal component regression (PCR)
G-QSAR method allows ease to interpretation, unlike conventional QSAR method which could only suggest important descriptors but does not reflect the site where it has to be optimized for further design of new compounds

Summary

Introduction

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). HIV can destroy so many of these cells that the body cannot fight off infections and leads to acquired immunodeficiency syndrome (AIDS), the last stage of HIV infection [3]. It is one of the world’s most significant public health challenges, in low- and middle-income countries. Human immunodeficiency virus (HIV) is a retrovirus because of the presence of an enzyme reverse transcriptase (RT), which possesses both RNA-dependent DNA polymerase (RDDP) and ribonuclease-H (RNase H) activities that work in tandem to convert viral genomic single-stranded RNA to double-stranded DNA by the process reverse transcription and by retrotransposon, mobile genetic elements are integrated into the DNA of the infected host cell to cause disease [9,10,11]. Reverse transcriptase inhibitors both nucleoside reverse transcriptase inhibitor (NRTI’s) and non-nucleoside reverse transcriptase inhibitor (NNRTI’s) are active against HIV which inhibits the process reverse transcription that leads to inhibition of formation of DNA from viral RNA (Fig. 1) for insertion into the host DNA sequence cause treatment of the disease [12, 13]

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