Integrative In Silico Profiling of Major Phytochemicals From a Sclerocarya birrea-Nauclea latifolia-Piper longum Mixture: Docking, Molecular Dynamics, ADMET, and Ligand-Based Target Prediction on Shared Pathways in Type 2 Diabetes Mellitus and Alzheimer's Disease.

Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) converge through metabolic dysfunction, inflammation, and impaired neuronal signaling, providing a rationale for multi-target intervention. This study aimed to identify phytochemicals from a Sclerocarya birrea-Nauclea latifolia-Piper longum mixture that may modulate this disease axis. Seven constituents were screened against AChE, BACE1, DPP4, glucokinase, GSK3β, and TACE using molecular docking and MM-GBSA rescoring. Prioritized complexes underwent triplicate 100-ns molecular dynamics simulations, post-MD MM-GBSA analysis, physicochemical/ADMET profiling, and ligand-based target prediction. Quercetin pentamethyl ether (QR-PME) emerged as the principal computational hit: its GSK3β and TACE complexes maintained stable structural and energetic behavior, with mean binding free energy estimates of -30.07 ± 0.06 and -34.24 ± 0.07 kcal/mol, respectively, matching those of the reference inhibitors (-30.05 ± 0.07 and -34.08 ± 0.06 kcal/mol). QR-PME satisfied Lipinski criteria and showed predicted intestinal absorption, although CYP inhibition liability and low blood-brain barrier permeability remain concerns. ABCG2 was its top predicted target, suggesting an experimentally unresolved link to amyloid-β transport. These findings generate a testable hypothesis that QR-PME may engage the metabolic-inflammatory-tau network connecting T2DM and AD, supporting biochemical, cellular, pharmacokinetic, and in vivo validation before its therapeutic applicability can be established.