Altered Gliclazide Metabolic Pathway and its Implications on Increased Therapeutic Response in CYP2C9*2: Molecular Dynamics simulation and Autodock Studies

Among sulfonylureas, gliclazide is prescribed to 80% of the diabetic population and mainly metabolized by CYP2C9 in Caucasians. Our data shows that the orientation of the substrate is changed and therefore, the site of oxidation with respect to heme-Fe is altered in *2. This leads to an altered metabolic pathway in *2 and it is a rate limiting step in gliclazide metabolism. Our results also show that the position of 7-propionate side chain of ring A and 6-propionate side chain of ring D is flipped in *2 and thus, the stability of heme and oxidative potential of substrate in the active binding pocket are reduced. In summary, the altered pathway, and instability of heme and the substrate in the active site are contributing to decreased metabolic activity consistent with greater therapeutic response observed in patients carrying CYP2C9 *2 allele.