Background: Inhibition of DPP-IV enzyme is an effective strategy for the treatment of type-2 diabetes mellitus, which involves the degradation of incretin hormones, glucagon like peptide (GLP-1) and gastric inhibitory polypeptide (GIP), being valuable in glucose tolerance and insulin secretion. A series of indole alkaloids from the medicinal plant Rauvolfia serpentina were identified as novel DPP-IV inhibitors using insilico prediction.
Objective: Our study is aimed to identify the novel DPP-IV inhibitors for the treatment of diabetes through system level investigation.
Method: Computational simulation techniques were used to analyze the molecular interaction between DPP-IV and a series of indole alkaloids. 3D structures of the indole alkaloids were retieved from Pubchem and PRIME KNApSAck databases. Online tools such as Molinspiration, ADMET and drug likeness properties of the indole alkaloids were investigated. Based on the minimum binding energy, stability of the docked complex was evaluated by molecular dynamic simulation.
Results: Among the 20 indole alkaloids investigated, molecular docking analysis revealed that yohimbine has higher binding energy compared to other indole alkaloids. It exhibits three π - π stacking interactions with amino acids in hydrophobic S1 and S2 pocket of DPP-IV receptor. Different parameters like binding energy, intermolecular energy, inhibition constant and H-bonding between the ligands & the target were used to determine the extent of inhibition. Interestingly, 5 intermolecular hydrogen bonds were formed between receptor-inhibitor complex to facilitate inhibition. The stability of the docked complex was confirmed by molecular dynamics simulation.
Conclusion: DPP-IV enzyme has a significant role in the regulation of glucose metabolism. Among the 20 indole alkaloids, yohimbine has a good binding energy towards DPP-IV and inhibits its function. Thus, yohimbine compound acts as a novel DPP-IV inhibitor for the treatment of type-2 diabetes.