| Summary: | The human liver enzyme CYP3A4 plays an important role in the biotransformation of xenobiotics from herbs to harmless and excretable metabolites. However, CYP3A4 catalytic activity may also produce more toxic metabolites. Predicting sites of metabolism (SOMs) in the xenobiotics may prevent unwanted CYP3A4 products. The evidence to explain the comprehensive biotransformation of major compounds from Centella asiatica and Orthosiphon stamineus is inadequate. The aim of the present study was to determine the specific interaction between CYP3A4 ferric-oxidative active sites and potential SOMs for the major chemical compounds of C. asiatica and O. stamineus. Molecular docking on CYP3A4 ferric-oxo (bound to the protoporphirin group, HEME–Fe3+–O-) was carried out using the CDOCKER simulation program to predict the SOMs for compounds from C. asiatica (asiaticoside, madecassoside, asiatic acid and madecassic acid) and O. stamineus (sinensetin, eupatorin and 5-hydroxy-6,7,3',4'-tetramethoxyflavone (5TMF)). Binding energies, residue–ligand interactions, and SOMs were obtained from the analysis. The molecular docking results also revealed that sinensetin, eupatorin, and 5TMF bound strongly to the CYP3A4 active site with binding energies of -22.44, -34.29, and -25.84 kcal/mol, respectively. Generally, the residues Arg106, Ile301, Ther309, Glu374 and Ala307 were identified to have the highest number of interactions with eupatorine, 5TMF and sinensetin. The SOM prediction for eupatorine showed interactions between the oxygen of the HEME iron (ferric-oxo) and the C-11 and O-4 atoms. The possible metabolism reactions were C-11-hydroxylation and O-4-demethylation. For 5TMF, the SOM prediction for interactions were at the C-13 and O-7 positions, which could undergo hydroxylation and O-demethylation reactions, respectively. The SOM of sinensetin was predicted at C-3’ and the possible metabolic reaction taking place would be hydroxylation. The present study concluded that the major compounds of O. stamineus have the potential to be metabolized by CYP3A4 through hydroxylation and O-demethylation reactions. These data may be useful for phytomedicine product development related to CYP3A4 biotransformation mechanisms. © 2021 Malaysian Institute of Chemistry. All rights reserved.
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