Ebelin lactone as the most promising neuroprotective compound from Bacopa monnieri extract targeting microtubule affinity regulation kinase-4 involved in Alzheimer’s disease: A Computational Study

Abstract

Abstract Background Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which amyloid-beta (Aβ) and tau tangles are vital in causing neurodegeneration. Only five FDA-approved drugs are available in the market which manages the symptoms. In this study, 52 novel phytochemicals were selected from the medicinal plant Bacopa monnieri, a medicinal plant with neuroprotective compounds.Objective The main aim of this study is to find the most promising compound inhibiting microtubule affinity regulation kinase 4 (MARK 4), which is involved in AD.Methods First, an ADMET analysis was conducted, and the selected compounds were molecularly docked against the MARK4-associated protein (5ES1). Based on the top five binding affinities, a molecular dynamics simulation was performed.Results Cucurbitacin E, oroxindin, ebelin lactone, cucurbitacin B, and bacosine showed binding affinity of more than − 10.0 kcal/mol, and molecular dynamics (MD) simulations of these molecules in complex with MARK4 was performed. Subsequent trajectory analysis for structural changes and end-state MMGBSA binding energy were performed for Cucurbitacin E, oroxindin, ebelin lactone, cucurbitacin B and bacosine. The MD simulation and MMGBSA calculations showed stable interactions between the screened molecules and MARK4.Conclusion This computational study predicted ebelin lactone to be the most promising compound from Bacopa monnieri that can be further developed as a drug to treat AD after pre-clinical and clinical studies.