Discovery of Potential DPP-4 Inhibitors from Cassia auriculata Through Dual Molecular Docking with GNINA and PLANTS

Abstract

Cassia auriculata is a medicinal plant recognized for its rich phytochemical composition and potential antidiabetic properties. However, the reliability of virtual screening is often influenced by the choice of docking algorithm and scoring function, leading to variations in compound prioritization. This study aimed to identify potential dipeptidyl peptidase-4 (DPP-4) inhibitors from C. auriculata phytochemicals using a consensus molecular docking strategy integrating GNINA and PLANTS. A total of 96 phytochemicals were docked against the DPP-4 crystal structure (PDB ID: 5Y7H), followed by Min–Max normalization of docking scores, consensus score calculation, Pearson and Spearman correlation analyses, and Venn analysis. GNINA and PLANTS produced significantly correlated normalized docking scores (Pearson r = 0.5829, p < 0.001; Spearman ρ = 0.5684, p < 0.001), indicating a moderate level of agreement despite their distinct scoring functions and search algorithms. Venn analysis identified 13 consensus compounds among the top-ranked candidates, while consensus scoring further prioritized Gambiriin A3, Asparanin B, Hordatine A, Albanol A, Isoorientin 7-glucoside, Epicatechin gallate, Campesteryl p-coumarate, Catechin, Orcein, and Auriculine, with Gambiriin A3 achieving the highest consensus score. Structural comparison revealed that the highest-ranked compounds predominantly possessed polyphenolic scaffolds characterized by multiple hydroxyl groups and aromatic ring systems, features commonly associated with favorable ligand–protein recognition. The integration of GNINA and PLANTS through score normalization and consensus ranking provides a systematic and reliable strategy for prioritizing potential natural DPP-4 inhibitors and identifies several promising phytochemicals from Cassia auriculata for subsequent experimental validation.