Dual PTP1B/DPP4 Inhibitory Potential of Agathosma betulina , Cymbopogon citratus , and Artemisia afra : Structure-Based Modeling of Phytochemical Leads and Essential Oil Bioassays

Type 2 diabetes mellitus (T2DM) remains a global health challenge characterized by insulin resistance and impaired incretin effects. This has spurred research into potential therapeutic agents from natural sources that can inhibit both protein tyrosine phosphatase 1B (PTP1B) and dipeptidyl peptidase 4 (DPP4), which are implicated in these diabetes effects. This study explored the therapeutic potential of Artemisia afra , Cymbopogon citratus , and Agathosma betulina through a dual approach: in vitro enzyme inhibition assays of their essential oils and computational modeling of their broader characteristic phytochemicals. Experimental results identified A. betulina essential oil as the most potent source, yielding IC 11 values of 27.26 μg/ml for PTP1B and 42.28 μg/ml for DPP4. To explore the wider polypharmacological potential of these botanical sources beyond the volatile fraction, computational screening of the plant metabolites was done, which highlighted nonvolatile flavonoids quercetin-3,7-diglucoside (Q37DG) and quercetin-7-O-glucoside (Q7G) as primary theoretical leads of A. betulina . MMGBSA analysis confirmed exceptional binding affinities for Q37DG (Δ G bind of −52.19 kcal/mol for PTP1B and −58.23 kcal/mol for DPP4), driven by van der Waals interactions and engagement with critical catalytic residues (Glu 117 , Asp 183 , Glu 206 , and Ser 630 ). DFT calculations established that molecular softness and LUMO energies are key descriptors of inhibitory reactivity. While genetic algorithm QSAR models ( R 2 > 0.88) validated the theoretical potency of these leads, pharmacokinetic profiling identified important translation bottlenecks, including low gastrointestinal absorption. Consequently, these flavonoids are characterized as early-stage pharmacological probes and structural templates for multi-target optimization. This is interdisciplinary research that identifies botanical polypharmacological leads for diabetes.