MULTITARGET NEUROPROTECTIVE POTENTIAL OF MYRISTICA MALABARICA AND SESBANIA GRANDIFLORA: AN INTEGRATED HR-LCMS, IN VITRO AND MOLECULAR DOCKING APPROACH IN DIABETES-ASSOCIATED COGNITIVE DYSFUNCTION

Abstract

Diabetes-associated cognitive decline (DACD) is a progressive neurodegenerative condition characterized by impairments in learning, memory, and executive function, primarily driven by chronic hyperglycemia-induced oxidative stress and neuroinflammatory pathways. Despite the availability of therapies, effective multitarget interventions remain limited. The present study was employed for an integrated experimental and computational approach to evaluate the hypothesis that methanolic bark extracts of Myristica malabarica and Sesbania grandiflora possess multifunctional neuroprotective properties capable of modulating multiple molecular targets involved in DACD. Phytochemical characterization was performed by quantification of total phenolic and flavonoid contents, followed by HR-LCMS for metabolite profiling. Identified phytoconstituents were subjected to in silico pharmacokinetic evaluation (SwissADME) to determine drug-likeness, gastrointestinal absorption, and blood–brain barrier permeability. Of all, twelve compounds satisfying ADME criteria were selected for molecular docking studies using AutoDock Vina against key DACD-related targets, including acetylcholinesterase (AChE), monoamine oxidase-B (MAO-B), cyclooxygenase-2 (COX-2), glycogen synthase kinase-3β (GSK-3β), and the Keap1–Nrf2 complex. Additionally, in vitro antioxidant and enzyme inhibition assays were conducted. Statistical analysis was performed using two-way ANOVA followed by Tukey’s post hoc test, with significance set at p < 0.05. HR-LCMS analysis identified multiple bioactive phytoconstituents, of which twelve demonstrated favorable pharmacokinetic properties, including high gastrointestinal absorption and blood–brain barrier permeability. Docking studies revealed that compounds M4(Androsta-4,9(11)-diene-3,17-dione), M8(Pirenperone), and M9(Drotaverine) exhibited strong binding affinities across multiple targets, with docking scores comparable to or exceeding standard drugs, donepezil and selegiline. In vitro assays demonstrated significant antioxidant and enzyme inhibitory activities (p < 0.01), including oxidative stress marker reduction and modulation of key enzymes associated with neurodegeneration and inflammation. The findings confirm that M. malabarica and S. grandiflora exhibit multifunctional and multitarget neuroprotective effects, supporting their potential as promising phytotherapeutic candidates for the management of DACD. Further in vivo validation, mechanistic studies, and formulation development are warranted to facilitate clinical translation.