Molecular docking studies on the inhibitory selectivity of cytochrome P450 2C9 by natural anti-arthritic compounds

Abstract

Abstract Five natural anti-arthritic compounds, diacerein, rhein, glucosamines (glucosamine 3-sulfate, G3S, and glucosamine 6-sulfate, G6S), and chondroitin disaccharide Δdi-4S (C4S) were docked individually to the defined binding site in CYP2C9 based on published crystal structure (PDB code: 1R9O) in this study. All investigated ligands bound deep in the active site pocket in close proximity to the heme. Except for chondroitin, all ligands bonded to residues found in critical secondary structures that formed the boundary of active site cavity including B-C loop, F helix, F-G loop and I helix. A total of 12 amino acids were involved in the binding and all were critical residues located in four out of six substrate recognition sites (SRSs) that have been identified as important substrate binding and catalysis regions in other CYP isoforms. The relatively more potent binding (lower CDOCKER interaction energy) observed for diacerein and rhein compared to glucosamines and C4S are likely due to two main factors: higher number of bonds between ligand molecule and CYP2C9 active site residues (14 versus 0–4), and direct hydrophobic interaction with the heme moiety. The binding residues identified in both diacerein and rhein were the residues that also bonded with sulfaphenazole, the specific and potent CYP2C9 inhibitor. Collectively, the in silico data from this study have provided insights into structural features of CYP2C9 critical for inhibition, and formed basis for further exploration of structural determinants for potency and specificity of some commonly used natural anti-arthritic compounds in CYP2C9 inhibition.