Metabolism of 8-aminoquinoline (8AQ) primaquine via aromatic hydroxylation step mediated by cytochrome P450 enzyme using density functional theory

Abstract

The 8-aminoquinoline (8AQ) drug Primaquine (PQ) is a prime anti-malarial drug, used in the treatment of malaria due to plasmodium vivax and plasmodium ovale. The hydroxylated metabolite of Primaquine is also responsible for many essential sexual transmission stages of Plasmodium falciparum. Present work reported the hydroxylation of Primaquine at ortho (2PQ) and para (4PQ) position by Cytochrome P450 enzyme. Density functional theory (DFT) is used to investigate the underlying pathway for aromatic hydroxylation at ortho (2PQ) and para (4PQ) position to produce 2-hydroxylated and 4-hydroxylated Primaquine respectively. Truncated model of putative active oxidant i.e. ferryl oxo porphyrin cation radical [FeIV(O)(heme+·)], which is referred as Cpd I in Cytochrome P450 enzymes has been used to mimic the behavior of enzyme. Substrate was modelled and reaction mechanism for two degenerate spin states namely doublet and quartet were performed to dwell the overall potential energy landscape, along with electronic structure and properties of reactant complex (RC), transition states (TS), intermediates (IM) and product complex (PC). The reaction was stepwise with electrophillic addition as the rate determining step, spin selectivity product formation was observed for hydroxylated product formation on high spin (HS) surface. All calculations are done for isolated reaction coordinate.