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

Abstract

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.