Reduced catalytic activity of human CYP2C9 natural alleles for gliclazide: Molecular dynamics simulation and docking studies

► The size of the gliclazide access entry channel to the protein active site is significantly reduced in *3 and *2/*3 mutants. ► The distance between the substrate hydroxylation site and the heme is >5 Å in *3 and *2/*3. ► The key residues, F100, F114 and F476, are absent in the interacting amino acid pocket of *3. ► Lack of stability of the active site residues R97 and R108 affects the stability of the heme and gliclazide in *2 and *3. ► Instabilities of heme and gliclazide at the active site affect their interaction, which in turn reduces the activity of mutants.