Discovery of Novel Peptides as DPP-IV Inhibitors: In Silico Screening, Molecular Dynamics Simulations, and Preliminary In Vitro Evaluation

The incretin hormone glucagon-like peptide-1 (GLP-1) has a significant role in glucose homeostasis, but its native form in the human body is highly susceptible to proteolytic degradation by dipeptidyl peptidase IV (DPP-IV). In this study, a peptide library was constructed from antimicrobial peptide databases to discover novel DPP-IV inhibitors based on structural similarity to that of native GLP-1.

A total of 26 candidate peptides were shortlisted and screened using <i>in silico</i> analysis, including molecular docking, pharmacokinetic profiling, and molecular dynamics simulations. Particularly, two of the candidate antimicrobial peptides showed potent binding affinity to DPP-IV, with free energy scores of −15.6 and −16.5 kcal/mol, surpassing the binding affinity of native GLP-1 for DPP-IV. These peptides also exhibited lower predicted binding affinities for the GLP-1 receptor (GLP-1R) than for DPP-IV, suggesting a potential selective inhibitory effect and, consequently, a lower predicted likelihood of interfering with native GLP-1 signaling.