The pharmacokinetic properties of HIV-1 protease inhibitors: A computational perspective on herbal phytochemicals

Abstract

Acquired Immune Deficiency Syndrome is the most severe phase of Human Immunodeficiency Virus (HIV) infection. Recent studies have seen an effort to isolate phytochemicals from plants to repress HIV, but less studies have focused on the effects of these phytochemicals on the activities of enzymes/transporters involved in the metabolism of these drugs, which is one of the aims of this study and, to examine the antiviral activity of these compounds against HIV-1 protease enzyme using computational tools. Centre of Awareness-Food Supplement (COA®-FS) herbal medicine, has been said to have potential anti-HIV features. SWISSTARGETPREDICTION and SWISSADME servers were used for determination of the enzymes/transporters involved in the metabolism of these protease inhibitor drugs, (PIs) (Atazanavir, Lopinavir, Darunavir, Saquinavir) and the effects of the selected phytochemicals on the enzymes/transporters involved in the metabolism of these PIs. Using Computational tools, potential structural inhibitory activities of these phytochemicals were explored. Two sub-families of Cytochrome P450 enzymes (CYP3A4 and CYP2C19) and Permeability glycoprotein (P-gp) were predicted to be involved in metabolism of the PIs. Six phytochemicals (Geranin, Apigenin, Fisetin, Luteolin, Phthalic acid and Gallic acid) were predicted to be inhibitors of CYP3A4 and, may slowdown elimination of PIs thereby maintain optimal PIs concentrations. Free binding energy analysis for antiviral activities identified four phytochemicals with favourable binding landscapes with HIV-1 protease enzyme. Epigallocatechin gallate and Kaempferol-7-glucoside exhibited pronounced structural evidence as potential HIV-1 protease enzyme inhibitors. This study acts as a steppingstone toward the use of natural products against diseases that are plagued with adverse drug-interactions.

Repurposing drugs and identification of inhibitors of integral proteins (spike protein and main protease) of SARS-CoV-2

“…Receptor-ligand interaction examined the molecular interactions between the bound molecules and the amino acid residues at the active sites of the enzyme (Chetty et al, 2016 ; Idowu et al, 2019 ). Figures 3–5 showed the 2 D visualisation of the interactions between the molecules and active site residues of COVID-19 M pro , COVID-19 S gp and the types of interactions (such as hydrogen bond, π-sigma, π-cation, π-Sulfur, π-alkyl, π-π stacked interaction, donor-donor interactions and Van der Waals (vdW) overlaps) observed in the interaction plots.…”

“…The MD simulation was performed as described by Idowu et al ( 2019 ). The simulations were performed using the GPU version provided with the AMBER package (AMBER 18), in which the FF18SB variant of the AMBER force field (Nair & Miners, 2014 ) was used to describe the systems.…”

Antiviral Properties of Flavonoids and Delivery Strategies

“…Mature HIV-1 protease exists as a 22 KDa homodimer, each one containing an Asp25 amino acid, which acts as the catalytic residues are able to hydrolyze peptide bonds on the Gag-Pol polyproteins into fully functional viral proteins, like reverse transcriptase and integrase. Kehinde et al (2019) [ 27 ] showed that the phytochemicals kaempferol-7- O -glucoside and EGCG were able to interact with HIV-1 protease, showing pronounced structural evidence as potential HIV-1 protease inhibitors ( Figure 4 ). Interestingly, phytochemicals can also be used to reduce the extrusion of antiviral drugs from infected cells.…”

“…Interestingly, phytochemicals can also be used to reduce the extrusion of antiviral drugs from infected cells. In fact, apigenin, fisetin and luteolin were able to slow down the elimination of the antiviral drugs atazanavir, lopinavir, darunavir and saquinavir, which target the viral protease of HIV-1 [ 27 ].…”

Phytochemicals as potential drug candidates for targeting SARS CoV 2 proteins, an in silico study

“…The extensive study on these natural phytochemicals also showed great results against other viruses like dengue, HIV, malaria, etc. [ 18 , 43 ]. Many of these compounds are indicated in the literature to have pharmacological properties [ 48 ].…”