Identification of potential neuroprotective compound from extract targeting microtubule affinity regulation kinase 4 involved in Alzheimer's disease through molecular dynamics simulation and MMGBSA.

OBJECTIVE

Alzheimer's disease (AD) is one of the most prevalent neurological ailments, affecting around 50 million individuals globally. The condition is characterized by nerve cell damage due to the formation of amyloid-beta plaques and neurofibrillary tangles. Only a few US Food and Drug Administration (FDA)-approved medications are available in the market which are devoid of side effects, thus, making it imperative to investigate new alternatives for countering this disease. According to a recent study, microtubule affinity regulation kinase 4 (MARK4) is attributed as one of the most promising drug targets for AD, thus, being selected for this study. Compounds from (Reishi mushroom) extracts were selected to be used as ligands for this study.

METHODS

In this study, the five most potent compounds from were selected and their absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis was performed, followed by molecular docking, and molecular dynamics simulation of each compound with MARK4 and supported by molecular mechanics generalized born surface area (MMGBSA) binding free energy calculations.

RESULTS

The promising compounds were selected based on their ADMET profile and interactions with the active site residues of MARK4. Based on docking scores of -9.1 and -10.3 kcal/ mol, respectively, stability assessment by molecular dynamics simulation, and MMGBSA calculations, ganoderic acid A and ganoderenic acid B were found to be the most promising compounds against MARK4 which will require further in vitro and in vivo validations.

CONCLUSION

Through this study, it is suggested that ganoderic acid A and ganoderenic acid B might be a class of promising compounds against AD, based on computational research, and can be further studied for preclinical and clinical studies.