An in silico pharmacological approach toward the discovery of potent inhibitors to combat drug resistance HIV‐1 protease variants

Abstract

Protease inhibitors (PIs) are crucial drugs in highly active antiretroviral therapy for human immunodeficiency virus-1 (HIV-1) infections. However, resistance owing to mutations challenge the long-term efficacy in the medication of HIV-1-infected individuals. Lopinavir (LPV) and darunavir (DRV), two secondgeneration drugs are the most potent among PIs, hustling the drug resistance when mutations occur in the active and nonactive site of the protease (PR).Herein, we strive for compounds that can stifle the function of wild-type (WT)HIV-1 PR along with four major single mutants (I54M, V82T, I84V, and L90M) instigating resistance to the PIs using in silico approach. Six common compounds are retrieved from six databases using combined pharmacophorebased and structure-based virtual screening methodology. LPV and DRV are docked and the binding free energy is calculated to set the cut-off value for selecting compounds. Further, to gain insight into the stability of the complexes the molecular dynamics simulation (MDS) is carried out, which uncovers two lead molecules namely NCI-524545 and ZINC12866729. Both the lead molecules connect with WT and mutant HIV-1 PRs through strong and stable hydrogen bond interactions when compared with LPV and DRV throughout the trajectory analysis. Interestingly, NCI-524545 and ZINC12866729 exhibit direct interactions with I50/50′ by replacing the conserved water molecule as evidenced by MDS, which indicates the credible potency of these compounds. Hence, we concluded that NCI-524545 and ZINC12866729 have great puissant to restrain the role of drug resistance HIV-1 PR variants, which can also show better activity through in vivo and in vitro conditions.

Structural insights into the RNA interaction with Yam bean Mosaic virus (coat protein) from Pachyrhizus erosus using bioinformatics approach

“…Comparative modeling's main benefit is that it aids in filling in gaps between available sequence and structural data by generating a reliable and accurate protein model [71]. The approach and parameters of MD simulation were adapted from our early studies to better comprehend the molecular function of unknown/hypothetical molecules [76][77][78][79][80][81].…”

An Innovative Sequence-to-Structure-Based Approach to Drug Resistance Interpretation and Prediction: The Use of Molecular Interaction Fields to Detect HIV-1 Protease Binding-Site Dissimilarities

“…The MIF module of IsoMIF was used to compute molecular interaction fields (MIFs) for six different chemical probe types (Figure 2): hydrophobic, aromatic, H-bond donor, Hbond acceptor, positive charge and negative charge. The pharmacophoric features shared by PIs (Wlodawer and Erickson, 1993;Nayak et al, 2019) highlight the importance of a conserved physicochemical environment in the binding site. Alterations of this environment are detected with the MIF probes (circled in Figures 2A,B) which allow for a quantification of changes caused by the presence of mutations.…”

“…Commercially available HIV-1 protease inhibitors (PIs) are competitive peptidomimetics with a core structural scaffold that mimics the tetrahedral transition state of HIV1-PR substrate. Although these drugs are chemically distinct, their active conformations are superimposable, and generally establish the same pharmacophoric interactions with their target (Wlodawer and Erickson, 1993;King et al, 2004;Qiu and Liu, 2011;Nayak et al, 2019). Many mutations in HIV1-PR translate into changes in the structure and binding site physicochemical environment, thus affecting the affinity of PIs and representing a hurdle to achieving long-term viral suppression (Irwin et al, 2016;Pawar et al, 2019;Wensing et al, 2019).…”

In silico approach on drug repurposing - Antimalarial drugs against HIV-1 protease

“…Since both PR inhibitors (PIs) with reverse transcriptase inhibitors are included in the therapy, reductions in AIDS-associated deaths were observed in the mid-90s (Pau and George, 2014). HIV PIs, hustling drug resistance when mutations arise to the active and nonactive site of the PR (Nayak, Chandra, and Singh, 2019). However, long-term usage of these drugs induce mutations that cause drug resistance that challenge the long-term effectiveness in the medication of HIV-1-infected individuals (Havlir and Gandhi, 2015).…”

“…The most effective medicines among HIV PIs are Lopinavir (LPV) and Darunavir (DRV). However, they are fostering drug resistance due to mutations occurring either at the active or non-active site of the protein (Nayak et al ., 2019). Particularly the continuous use of these drugs induces mutations leading to drug resistance, which challenge long-lasting efficacy in the medication of HIV-1-infected individuals (Havlir and Gandhi, 2015).…”