The medicinal herb Aspalathus linearis (rooibos) is globally recognized in type-2 diabetes mellitus (T2DM) treatment due to its known and distinctive compounds. This work utilized network pharmacology (NP) coupled with molecular dynamics simulation in gaining new insight into the anti-diabetic molecular mechanism of action of rooibos teas. It looked at the interactions between rooibos constituents with various relevant protein receptors and signaling routes associated with T2DM progression. The initial analysis revealed 197 intersecting gene targets and 13 bioactive rooibos constituents linked to T2DM. The interactions between proteins and compounds to the target matrix were generated with the Cystoscope platform and STRING database. These analyses revealed intersecting nodes active in T2DM and hypoxia-inducible factor 1 (HIF-1) as an integral receptors target. In addition, KEGG analysis identified 11 other pathways besides the hub HIF-1 signaling route which may also be targeted in T2DM progression. In final molecular docking and dynamics simulation analysis, a significant binding affinity was confirmed for key compound-protein matrices. As such, the identified rooibos moieties could serve as putative drug candidates for T2DM control and therapy. This study shows rooibos constituents’ interaction with T2DM-linked signaling pathways and target receptors and proposes vitexin, esculin and isovitexin as well as apigenin and kaempferol as respective pharmacologically active rooibos compounds for the modulation of EGFR and IGF1R in the HIF-1 signaling pathway to maintain normal homeostasis and function of the pancreas and pancreatic β-cells in diabetics.

Purpose The therapeutic use of oral hypoglycaemic agents in the management of type-2 diabetes mellitus (T2DM) is without adverse effects; thus, calls for alternative and novel candidates from natural products in medicinal plants. Method The study explored molecular docking and molecular dynamics (MD) simulation approaches to identify key antidiabetic metabolites from Crescentia cujete. Results Molecular docking results identified four and/or five best compounds against each target enzyme (alpha-glucosidase, dipeptidyl peptidase-IV, aldose reductase, and protein tyrosine phosphatase-1B (PTP-1B)) implicated in diabetes. The resulting complexes (except against PTP-1B) had higher docking scores above respective standards (acarbose, Diprotin A, ranirestat). The MD simulation results revealed compounds such as benzoic acid (-48.414 kcal/mol) and phytol (-45.112 kcal/mol) as well as chlorogenic acid (-42.978 kcal/mol) and naringenin (-31.292 kcal/mol) had higher binding affinities than the standards [acarbose (-28.248 kcal/mol), ranirestat (-21.042 kcal/mol)] against alpha-glucosidase and aldose reductase, respectively while Diprotin A (-45.112 kcal/mol) and ursolic acid (-18.740 kcal/mol) presented superior binding affinities than the compounds [luteolin (-41.957 kcal/mol and naringenin (-16.518 kcal/mol)] against DPP-IV and PTP-1B respectively. Conclusion While isoflavone (alpha-glucosidase), xylocaine (DPP-IV), luteolin (aldose reductase,) and chlorogenic acid (PTP-1B) were affirmed as the best inhibitors of respective enzyme targets, luteolin, and chlorogenic acid may be suggested and proposed as probable candidates against T2DM and related retinopathy complication based on their structural stability, compactness and affinity for three (DPP-IV, aldose reductase, and PTP-1B) of the four targets investigated. Further studies are warranted in vitro and in vivo on the antihyperglycaemic effects of these drug candidates.