Cryptotanshinone and 15,16-dihydrotanshinone I from Salvia miltiorrhiza: integrated in vitro and computational evaluation of their antidiabetic potential.

Salvia miltiorrhiza Bunge (Lamiaceae) is a traditional medicinal plant rich in bioactive tanshinones with diverse pharmacological properties. However, comparative information regarding experimentally measured activity and computational interaction profiles of individual tanshinones remains limited. This study aimed to compare cryptotanshinone (1) and 15,16-dihydrotanshinone I (2), isolated from S. miltiorrhiza, using an integrated in vitro and computational approach. The compounds were obtained through activity-informed phytochemical fractionation and evaluated for inhibition of α-glucosidase at 3, 10, and 30 µM. Concentration-response data were analyzed by nonlinear regression. Their computational interaction profiles were further investigated by molecular docking against selected diabetes-related proteins, followed by molecular dynamics simulations, MM/GBSA calculations, and in silico ADMET/toxicity predictions. Compound 2 showed stronger yeast α-glucosidase inhibition than compound 1, with IC50 values of 7.76 µM (95% CI: 7.43-8.10 µM) and 10.64 µM (95% CI: 9.62-11.77 µM), respectively (p < 0.0001). In contrast, the docking preferences were target dependent: compound 1 produced more negative docking scores for human MGAM-C, PTP1B, and glucokinase, whereas compound 2 ranked more favorably for GSK-3β, NLRP3, PPAR-γ, and GLP-1R. This lack of concordance between yeast α-glucosidase inhibition and human MGAM-C docking indicates that docking rankings should not be interpreted as direct evidence of target inhibition. Molecular dynamics simulations revealed target- and ligand-dependent binding behavior, while MM/GBSA calculations yielded negative estimated binding free energies for the investigated complexes. Although both compounds satisfied Lipinski's rule, the predicted low gastrointestinal absorption, extensive plasma protein binding, CYP inhibition, and toxicity alerts indicated important developability limitations. Overall, compound 2 exhibited the stronger experimentally measured yeast α-glucosidase inhibition, whereas the computational findings provide target-specific hypotheses rather than confirming multitarget antidiabetic activity. Further studies using purified human enzymes, mechanistic assays, experimental pharmacokinetic and toxicological evaluations, and in vivo models are required to establish their biological and therapeutic relevance.