Integrated Phytochemical and Multi-Target Enzyme Inhibition Profiling of Nilgiris Lichens: Novel Insights into Natural Antidiabetic Therapeutics

Lichens represent an underexplored source of bioactive metabolites with therapeutic relevance in metabolic disorders. This study investigated lichens collected from the Nilgiris (Tamil Nadu, India) to identify antidiabetic compounds through an integrated phytochemical, biochemical, and computational approach. Methanolic and ethyl acetate extracts demonstrated strong antioxidant activity (DPPH, ORAC) and high phenolic/flavonoid content. Multi-target enzyme inhibition assays revealed significant suppression of α-amylase, α-glucosidase, pancreatic lipase, and protein tyrosine phosphatase (PTP1B), with some extracts achieving >80% inhibition. GC–MS profiling identified key metabolites, including 2,5-dihydroxyterephthalic acid, diospyrol, O-(4-biphenylylcarbonyl) benzoic acid, and lecanoric acid. In silico docking confirmed strong binding affinities of these compounds with catalytic sites, in several cases surpassing standard inhibitors (acarbose, orlistat). Pharmacokinetic and toxicity prediction further supported their drug-likeness and safety. To our knowledge, this is the first systematic report on Nilgiris lichens as multi-target modulators of carbohydrate and lipid metabolism, positioning their metabolites as promising candidates for natural antidiabetic drug discovery.