Inhibiting α‐glucosidase, a key enzyme in carbohydrate hydrolysis, can potentially control diabetes mellitus. Although commercially available drugs effectively lower blood glucose levels to mitigate hyperglycemia, their associated gastrointestinal side effects necessitate the exploration of explicit inhibitors with minimal side effects. We studied a library of 80 secondary metabolites ascribed to their antidiabetic properties and screened the most potent inhibitors using a comprehensive in silico approach, including molecular docking, DFT study, MD simulation, PCA, MMPBSA calculation, and pharmacokinetic analysis. Scolopianate A and ponasterone A emerged as potent α‐glucosidase inhibitors, forming hydrogen bonds with the catalytic diad and exhibiting prominent binding affinities of −8 kcal/mol. Further analyses encompassed significant reactivity at the catalytic site and stable protein‐ligand complexes, as asserted by 100 ns RMSD, RMSF, R_g, SASA, H‐bond, and PCA‐based free energy landscape analysis. The subsequent analysis of MMPBSA indicating a higher binding free energy of these compounds compared to reference ligand, acarbose further strengthened the validity of these findings. Furthermore, drug‐like behavior and favorable ADMET profiles affirmed scolopianate A and ponasterone A as robust α‐glucosidase inhibitors. These findings highlight their promise for future drug development targeting α‐glucosidase inhibition in diabetes management; however, more research needs to be conducted.

Globally, obesity is a serious health concern that causes numerous diseases, including type 2 diabetes, hypertension, cardiovascular diseases, etc. Medicinal plants have been used to aid in weight loss since ancient times. Thus, this research is focused on the exploration of pancreatic lipase inhibitory activity and secondary metabolite profiling of Bergenia ciliata, Mimosa pudica, and Phyllanthus emblica, selected based on an ethnobotanical survey. The lipase inhibition was investigated using 4-nitrophenyl butyrate (p-NPB) as a substrate. To uncover further therapeutic potentials of these medicinal plants, antimicrobial activity and minimum inhibitory concentration (MIC) of the extracts were also determined. The ethyl acetate plant extracts showed higher antimicrobial activity against Staphylococcus aureus, Escherichia coli, Salmonella typhi, and Shigella sonnei. The MIC of ethyl acetate extracts of medicinal plants considered in this study ranges from 1.56 to 6.25 mg/mL. The hexane fraction of Mimosa pudica and Phyllanthus emblica showed a higher lipase inhibitory activity as compared to others, with IC₅₀ values of 0.49 ± 0.02 and 2.45 ± 0.003 mg/mL, respectively. In the case of Bergenia ciliata, the methanolic extract inhibited lipase more effectively than others, with an IC₅₀ value of 1.55 ± 0.02 mg/mL (IC₅₀ value of orlistat was 179.70 ± 3.60 µg/mL). A mass spectrometry analysis of various solvent/solvent partition fractions (extracts) revealed 29 major secondary metabolites. The research offers a multitude of evidence for using medicinal plants as antiobesity and antimicrobial agents.

Obesity remains a global health concern, and inhibiting human pancreatic lipase (EC3.1.1.3), a key enzyme in dietary fat breakdown and absorption, is an effective therapeutic approach. However, current lipase inhibitors such as orlistat are often associated with adverse gastrointestinal side effects and poor patient compliance. As a safer and multifunctional alternative, we investigated a library of naturally derived polyphenols known for their enzyme inhibitory activity and metabolic benefits, including anti-inflammatory effects, enhanced insulin sensitivity, and modulation of gut microbiota—offering a synergistic approach to obesity management. This study explores the dynamic and mechanistic inhibitory potential of polyphenol-based HPL inhibitors through an extensive in silico approach, aiming to identify explicit, low-toxicity inhibitors that serve as multi-benefit scaffolds for next-generation anti-obesity therapeutics. Significant binding affinity and interactions with a catalytic triad (SER 152, HIS 263, and ASP 176) of HPL through molecular docking, alongside higher MM/GBSA values of − 53.29, − 52.76, and − 53.37 kcal/mol, identified (-)-epigallocatechin-3-O-p-coumarate, (+)-catechin-3-O-gallate, and (−)-epicatechin-3-O-(3’-O-methyl gallate), respectively, as potent leads. The DFT study and molecular dynamics simulation affirmed the strong reactivity of these compounds in the catalytic site of HPL and a stable protein-ligand complex over 100 ns. FEL, PCA, and DCCM analysis also demonstrated these protein-ligand complexes’ stable dynamic behavior and conformational changes. Additionally, post-simulation MMPBSA analysis revealed higher binding free energies of − 59.46, − 56.54, and − 48.48 kcal mol⁻¹ for these complexes, indicating the formation of thermodynamically more stable complexes. Their favorable ADMET and drug-likeness pharmacokinetic properties further support their potential as effective HPL inhibitors with the potential for obesity control. The finding highlights (−)-epigallocatechin-3-O-p-coumarate, (+)-catechin-3-O-gallate, and (−)-epicatechin-3-O-(3’-O-methyl gallate) as promising low-toxicity, multi-benefit candidates for obesity management, paving the way for next-generation plant-based therapeutics. AbstractSection Graphical abstract

Background: Inhibiting human pancreatic lipase (EC3.1.1.3), a key enzyme in dietary fat breakdown and absorption, is an effective therapeutic approach for obesity control. Polyphenols, due to their multifaceted structure, enhance insulin sensitivity, reduce inflammation, and modulate gut microbiota, offering synergistic effects in controlling obesity. Methods: Considering the adverse side effects associated with current anti-obesity therapeutics, we explored a library of polyphenols known for their antiobesity properties to explicitly potent HPL inhibitors through extensive in-silicostudy including molecular docking, DFT, MD simulation, PCA, DCCM-based conformational analysis and pharmacokinetic analysis. Results: Significant binding affinity and interactions with catalytic triad (SER 152, HIS 263, and ASP 176) of HPL through molecular docking, alongside higher MM/GBSA values of -53.29, -52.76, and -53.37 kcal/mol, identified (-)-epigallocatechin-3-O-p-coumarate, (+)-catechin-3-O-gallate, and (-)-epicatechin-3-O-(3'-O-methyl gallate), respectively, as potent leads. The DFT study and molecular dynamics simulation affirmed the strong reactivity of these compounds in the catalytic site of HPL and stable protein-ligand complex over 100 ns. FEL, PCA, and DCCM analysis also demonstrated these protein-ligand complexes' stable dynamic behavior and conformational changes. Moreover, post-simulation MMPBSA analysis indicated higher binding free energy and favorable ADMET and drug-likeness pharmacokinetic properties asserted these lead potentials as explicit HPL inhibitors with potential for obesity control. Conclusion: To sum up, (-)-epigallocatechin-3-O-p-coumarate, (+)-catechin-3-O-gallate, and (-)-epicatechin-3-O-(3'-O-methyl gallate) are identified as promising HPL inhibitors, with potential application in managing obesity due to their stable interaction with the enzyme and favorable pharmacokinetic characteristics.