Computational drug design strategies applied to the modelling of human immunodeficiency virus-1 reverse transcriptase inhibitors

Abstract

Reverse transcriptase (RT) is a multifunctional enzyme in the human immunodeficiency virus (HIV)-1 life cycle and represents a primary target for drug discovery efforts against HIV-1 infection. Two classes of RT inhibitors, the nucleoside RT inhibitors (NRTIs) and the nonnucleoside transcriptase inhibitors are prominently used in the highly active antiretroviral therapy in combination with other anti-HIV drugs. However, the rapid emergence of drug-resistant viral strains has limited the successful rate of the anti-HIV agents. Computational methods are a significant part of the drug design process and indispensable to study drug resistance. In this review, recent advances in computer-aided drug design for the rational design of new compounds against HIV-1 RT using methods such as molecular docking, molecular dynamics, free energy calculations, quantitative structure-activity relationships, pharmacophore modelling and absorption, distribution, metabolism, excretion and toxicity prediction are discussed. Successful applications of these methodologies are also highlighted.

Molecular Docking Studies of HIV-1 Resistance to Reverse Transcriptase Inhibitors: Mini-Review

“…Molecular docking is one of the broadly used computational procedures in the computer-aided drug design [ 9 , 12 , 51 , 52 ]. Typically, a set of ligands is positioned within the protein’s binding site (for more details of this method, see [ 51 , 52 , 53 , 54 , 55 ]).…”

“…The 3D structure of mutant RT optimization can be done by energy minimization or, preferably, by simulation of molecular dynamics using AMBER (University of California, San Francisco, CA, USA, ), GROMACS (GROMACS University of Groningen, Netherlands, ) or other packages [ 55 ]. Other methods and applications of molecular docking in the field of HIV reverse transcriptase inhibition are reviewed partially in [ 9 , 12 , 13 ]. There are some approaches directed to the estimation of a binding energy minimum through the generation of several possible conformations of ligand in the protein active site.…”

“…Molecular modeling allows explaining the molecular mechanisms of resistance associated with a particular three-dimensional complex of RT and a small molecule. This method may also be used for revealing new compounds that are active against the mutant forms of HIV-1 RT [ 9 ]. Docking-based approaches are useful for predicting the importance of mutations for the resistance of HIV-1 if a data set of the known drugs is employed to perform the molecular docking procedure [ 10 ].…”

“…Molecular docking can be carried out if data are available on, at least, one complex of protein-ligand (protein-low molecular weight compound) in contrast to the structure-property relationship analysis, which requires the data on a set of low molecular weight compounds and their impact on a particular protein. The molecular docking approaches are repeatedly reviewed [ 9 , 11 , 12 , 13 ]. However, recent molecular docking approaches aimed at studying the interaction of small molecules with the resistant RT HIV-1 variants, are not widely discussed.…”

Computational Approaches to Develop Isoquinoline Based Antibiotics through DNA Gyrase Inhibition Mechanisms Unveiled through Antibacterial Evaluation and Molecular Docking

“…Obviously, computer‐aided drug discovery (structure‐based/ligand‐based methods) being the economical method for more than two decades. Significantly, computational tools are taking an important part in the identification of therapeutically important small molecules ,. Most importantly, the need for the effective computer‐aided antibiotic screening is much awaited/needed all through the years, because, pathogenic bacteria are one of the main causative agents that are also taking a vital role in global human mortality (WHO).…”