CytochromeP450 isoenzyme specificity in the metabolism of anti-malarial biguanides: molecular docking and molecular dynamics analyses

Abstract

Anti-malarial proguanil (1) and phenoxypropoxy biguanide derivatives (2–9) are prodrugs. Their efficacy is directly proportional to the quantity of active triazine metabolites produced from these prodrugs. Detailed molecular docking analyses for all nine drug candidates in the active site of CYP3A4, CYP2D6, and CYP2C19 were carried out under the influence of induced-fit effect of ligand during molecular dynamic simulations. We have developed a strategy based on docking pose clusters to quantify the production of active metabolites for this class of molecules. For all drugs, site of metabolism based clusters of docking poses were prepared in both phases of the molecular docking analyses and correlated with the percentage of metabolites generated in the pooled human liver microsomes study. The total numbers of docking poses representing active metabolite formation were found to be well correlated with the experimental results in post-induced fit docking analyses. This strategy was first validated using proguanil, PS-15 and JPC-2056. Further, this methodology was employed to correlate the theoretically predicted metabolite formation of 4–9 to the experimentally estimated values which further led to clues on isoenzyme specificity in producing the metabolites. Binding requirements of these leads in the active sites of CYPs were also explored in this study.