Molecular dynamic mechanism(s) of inhibition of bioactive antiviral phytochemical compounds targeting cytochrome P450 3A4 and P-glycoprotein.

P-glycoprotein (ABCB1) and cytochrome P450 3A4 (CYP3A4) metabolize almost all known human immunodeficiency virus' protease inhibitor drugs (PIs). Over induction of these proteins' activities has been linked to rapid metabolism of PIs which are then pumped out of the circulatory system, eventually leading to drug-resistance in HIV-positive patients. This study aims to determine, with the use of computational tools, the inhibitory potential of four phytochemical compounds (PCs) (epigallocatechin gallate (EGCG), kaempferol-7-glucoside (K7G), luteolin (LUT) and ellagic acid (EGA)) in inhibiting the activities of these drug-metabolizing proteins. The comparative analysis of the MM/GBSA results revealed that the binding affinity (ΔGbind) of EGCG and K7G for CYP3A4 and ABCB1 are higher than LUT and EGA and fall between the ΔGbind of the inhibitors of CYP3A4 and ABCB1 (Ritonavir (strong inhibitor) and Lopinavir (moderate inhibitor)). The structural analysis (RMSD, RMSF, RoG and protein-ligand interaction plots) also confirmed that EGCG and K7G showed similar inhibitory activities with the inhibitors. The study has shown that EGCG and K7G have inhibitory activities against the two proteins and assumes they could decrease intracellular efflux of PIs, consequently increasing the optimal concentration of PIs in the systemic circulation.Communicated by Ramaswamy H. Sarma.