Review highlights significant variability in molecular docking of natural DPP-4 inhibitors for type 2 diabetes

Dipeptidyl peptidase-4 (DPP-4) is a key therapeutic target for type 2 diabetes mellitus (T2DM) due to its role in regulating incretin hormones and glucose homeostasis. While existing DPP-4 inhibitors are widely used, their moderate efficacy necessitates the discovery of novel compounds. Natural products offer a rich source of diverse bioactive molecules, and computational tools like molecular docking have become essential for identifying potential new inhibitors, bridging the gap between traditional medicine and modern drug discovery.

This comprehensive review systematically analyzed over 150 studies on molecular docking of natural compounds as DPP-4 inhibitors. The researchers critically evaluated these studies based on their specific docking methodologies, the selection of DPP-4 protein structures (e.g., 1X70, 6B1E), and the validation strategies employed. The primary objective was to summarize current practices, identify common trends, and highlight methodological gaps in the in silico screening of natural products for T2DM treatment.

The review revealed substantial variability in the computational protocols used across the over 150 studies evaluated. Frequently utilized protein structures for docking included ligand-bound DPP-4 models such as 1X70 and 6B1E. Among the natural compounds investigated, flavonoids constituted the most extensively studied class, followed by alkaloids, phenolics, terpenoids, and peptides. Despite numerous reports of favorable binding interactions within the DPP-4 active site, a significant gap was identified:

Many studies relied solely on docking results without further experimental validation, with limited use of molecular dynamics simulations or in vitro assays. This highlights a critical need for more robust validation to enhance the reliability and translational relevance of these in silico findings.