The re-emerging Zika virus (ZIKV) is an arthropod-borne virus that has been described to have explosive potential as a worldwide pandemic. The initial transmission of the virus was through a mosquito vector, however, evolving modes of transmission has allowed the spread of the disease over continents. The virus has already been linked to irreversible chronic central nervous system conditions. The concerns of the scientific and clinical community are the consequences of Zika viral mutations, thus suggesting the urgent need for viral inhibitors. There have been large strides in vaccine development against the virus but there are still no FDA approved drugs available. Rapid rational drug design and discovery research is fundamental in the production of potent inhibitors against the virus that will not just mask the virus, but destroy it completely. In silico drug design allows for this prompt screening of potential leads, thus decreasing the consumption of precious time and resources. This study demonstrates an optimized and proven screening technique in the discovery of two potential small molecule inhibitors of ZIKV Methyltransferase and RNA dependent RNA polymerase. This in silico 'per-residue energy decomposition pharmacophore' virtual screening approach will be critical in aiding scientists in the discovery of not only effective inhibitors of Zika viral targets, but also a wide range of anti-viral agents.
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.
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