Discovering bioactive pharmaceuticals from natural products for type 2 diabetes mellitus using network pharmacology, molecular docking, and molecular dynamics

Type 2 diabetes mellitus (T2DM) is a global health challenge that requires new therapeutic approaches. Natural compounds from botanical sources offer promise as alternative treatments due to their multifaceted bioactivity and favourable safety profiles. This study employs an in-silico methodology to evaluate their therapeutic potential by targeting genes associated with T2DM. Bioactive natural compounds were screened and sourced from Natural Product Activity and Species Source Database (NPASS) and ZINC12 databases against 14 T2DM-associated genes (GPD2, IRS1, PPARG, IAPP, GCK, ABCC8, MAPK8, MTNR1B, AKT2, PTPN1, INSR, AMPK, GAA, and SLC2A4). Molecular docking assessed binding affinities, while pharmacokinetic and ADMET profiles were predicted. Comparative analyses with approved drugs from DrugBank, network pharmacology approaches, and molecular dynamics simulations further evaluated their therapeutic potential. 72 natural compounds exhibited superior or comparable binding affinities to standard drugs of which, 17 ligands -Moracin D, Moracin P, Plantagineoside A, Pyrene (carcinogenic), Curcumin, Rohitukine, Berberine Chloride, Berberrubine, Apigenin, Emodin, Chelerythrine, Alvocidib, A-443,654, Xambioona, Altertoxin I, Ursolic Acid, and Oleanolic Acid -were selected as top candidates for further analysis. ADME/T analyses highlighted Pyrene, Guggulsterone, Melatonin, Gefitinib, Apigenin, Rotenone, Curcumin, Bavachinin A, Bavachinin, and Quinidine as particularly promising in terms of superior ADME and oral bioavailability. Four ligands-2-Tert-Butyl-6-[(3-Tert-Butyl-2-Hydroxy-5-Methylphenyl)Methyl]-4-Methylphenol, 4-(2-Phenylpropan-2-Yl)Phenol, Phenothiazine, and 2-Naphthalen-1-Ylacetic Acid- showed notable minimal toxicity. Chelerythrine, Emodin, Rohitukine, A-443,654, and Alvocidib demonstrated multi-target networking interactions. Molecular dynamics simulations of the 17 highest-ranked complexes (500 ns) demonstrated stable RMSD values (4.39-5.33 Å), strong hydrogen bonding, and favorable energetic profiles. Particularly, Moracin P, Moracin D, Plantagineoside A, Chelerythrine, Alvocidib, and Ursolic Acid showed the most stable MD trajectories and highly favorable free energy as promising lead candidates. This study highlights the effectiveness of in-silico techniques to identify natural products as prospective alternative or adjunct therapies for T2DM. Further experimental validation is necessary to confirm compounds' efficacy and safety, paving the way for future clinical investigations.