Integrative approaches in HIV‐1 non‐nucleoside reverse transcriptase inhibitor design

Abstract

The design of inhibitors for human immunodeficiency virus type-1 reverse transcriptase (HIV-1 RT) is one of the most successful approaches for the treatment of HIV infections. Among the HIV-1 RT inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs) constitute a prominent drug class, which includes nevirapine, delavirdine, efavirenz, etravirine, and rilpivirine approved for clinical use. However, the efficiency of many of these drugs has been undermined by drug-resistant variants of HIV-1 RT, and it therefore becomes inevitable to design novel drugs to cope with resistance. Here, we discuss various drug design strategies, which include traditional medicinal chemistry, computational chemistry, and chemical biology approaches. In particular, computational modeling approaches, including machine learning, empirical descriptors-based, force-field, ab initio, and hybrid quantum mechanics/molecular mechanics-based methods are discussed in detail. We foresee that these methods will have a major impact on efforts to guide the design and discovery of the next generation of NNRTIs that combat RT multidrug resistance.

A computational study for rational HIV-1 non-nucleoside reverse transcriptase inhibitor selection and the discovery of novel allosteric pockets for inhibitor design

“…As an error-prone HIV-1 RT may eventually escape the four available NNRTIs, our further research found a potential candidate pocket (i.e. P2) in the p51 subunit that showed promise as a new druggable site, to which new inhibitors can be designed against HIV-1 [ 35 ].…”

Computational investigation on Andrographis paniculata phytochemicals to evaluate their potency against SARS-CoV-2 in comparison to known antiviral compounds in drug trials

“…In order for a ligand to serve as a therapeutic molecule, it has to bind to a specific catalytic site with significant binding affinity. In certain cases, the ligands bind to allosteric sites (as in non-nucleoside reverse transcriptase inhibitors in HIV (Poongavanam et al, 2018)) which leads to specific structural/conformational changes in the binding site causing the modulation or inhibition of substrate binding. We speculate that in the case of spike protein-ACE2 complex, even though the ligands are not binding to interfacial regions, they may indirectly affect the binding of spike protein to ACE-2 receptors.…”

Structure-Based Optimization of N-Substituted Oseltamivir Derivatives as Potent Anti-Influenza A Virus Agents with Significantly Improved Potency against Oseltamivir-Resistant N1-H274Y Variant

“…The theory and methodology have been described in detail elsewhere. [61][62][63][64][65] The binding free energies (ΔG bind ) for all protein−ligand complexes were calculated using the MMPBSA.py script 66 in Amber12.…”