Computational identification of a marine derived dual inhibitor for type 2 diabetes mellitus using integrated in silico approaches

The multi-factorial metabolic disorder, type 2 diabetes mellitus (T2DM) is caused by inadequate insulin signaling and dysregulated incretin-mediated glucose homeostasis, resulting in complementary dual-target therapies. Using an integrated in-silico pipeline, it searched for marine compounds that act as dual inhibitors of PTP1B and DPP-4. After curation, 35,034 invalid entries were deleted from 74,507 marine compounds, followed by physicochemical filtering (MW 200–350 Da) to yield 4,500 compounds and Lipinski refinement to 3,395 ligands. PubChem mapping validated 2,230 compounds (name/CID-matched), while SwissADME and pkCSM toxicity filters selected 63 structure-based screening candidates. The highest docking affinities for human PTP1B (4I8N) and DPP-4 (5KBY) reached −8.7 and −9.0 kcal/mol, respectively, calculated using inhibitor-defined active-site grids in AutoDock Vina. Due to favorable docking and stable complex behavior in 200 ns GROMACS 2024.4 MD simulations, RMSD, RMSF, SASA, Rg, PCA, DCCM, and MM-GBSA analyses, CID_5281663 (1,3,5-trihydroxyxanthone) was chosen as the most consistent dual-target candidate. MM-GBSA calculations further supported stable binding, with total binding free energies of −5955.51 ± 54.24 and −8895.41 ± 202.85 for PTP1B and DPP-4 complexes, respectively. The top ligand’s frontier orbital properties were further examined using DFT (B3LYP/6–31+G(d,p)), and downstream biological relevance was contextualized using Reactome pathway mapping of the insulin and incretin signaling cascade. Overall, the combined screening and modelling methodology suggests 1,3,5-trihydroxyxanthone (CID_5281663) from soft coral Lobophytum microlobulatum as a promising marine-derived dual PTP1B/DPP-4 inhibitor candidate, warranting experimental validation for T2DM therapy.