Wang_2019_ACS.Catal_9_2292

Vildagliptin (VIL) and saxagliptin (SAX) are two covalent drugs for the treatment of type 2 diabetes mellitus. The principal pharmacological effects of VIL and SAX are known to arise from their biochemical reactions at the active site of dipeptidyl peptidase-4 (DPP-4), a serine protease that rapidly inactivates incretin hormones in plasma. However, the details of the catalytic mechanisms and the origin of the different pharmacokinetics behavior for the two scaffold-similar drugs are less clear. By employing quantum mechanical/molecular mechanical molecular dynamics simulations in this work, it is illuminated that the catalytic process involves two major steps: reversible covalent bonding which covalently modifies the antidiabetic target DPP-4 and irreversible hydrolysis reaction which converts the drugs into inactive metabolites. The reaction free energy profiles indicate that VIL is dissociated from DPP-4 mainly through the hydrolysis pathway, while SAX overwhelmingly through the reverse process of covalent bonding. Therefore, the inhibition is pseudoirreversible for VIL, while reversible for SAX. Further comparative studies reveal that the 4,5-methylene substituent of pyrrolidine ring in SAX is responsible for the different dissociation kinetics features and its higher inhibitory activity compared to the VIL. All these findings are in agreement with the previously reported experimental results and guidable for further covalent drug design toward DPP-4.