Inhibition of Microtubule Affinity Regulating Kinase 4 by Metformin: Exploring the Neuroprotective Potential of Antidiabetic Drug through Spectroscopic and Computational Approaches
Ghulam Md. Ashraf,
Debarati DasGupta,
Mohammad Zubair Alam,
Saleh S. Baeesa,
Badrah S. Alghamdi,
Firoz Anwar,
Thamer M. A. Alqurashi,
Sharaf E. Sharaf,
Waleed Al Abdulmonem,
Mohammed A. Alyousef,
Fahad A. Alhumaydhi,
Anas Shamsi
Affiliations
Ghulam Md. Ashraf
Department of Medical Laboratory Sciences, College of Health Sciences, and Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates
Debarati DasGupta
College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109, USA
Mohammad Zubair Alam
Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
Saleh S. Baeesa
Division of Neurosurgery, College of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia
Badrah S. Alghamdi
Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
Firoz Anwar
Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
Thamer M. A. Alqurashi
Department of Pharmacology, Faculty of Medicine, King Abdul-Aziz University, Rabigh 21589, Saudi Arabia
Sharaf E. Sharaf
Pharmaceutical Chemistry Department, College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia
Waleed Al Abdulmonem
Department of Pathology, College of Medicine, Qassim University, P.O. Box 6655, Buraydah 51452, Saudi Arabia
Mohammed A. Alyousef
Division of Neurosurgery, College of Medicine, King Abdulaziz University Hospital, Jeddah 21589, Saudi Arabia
Fahad A. Alhumaydhi
Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 52571, Saudi Arabia
Anas Shamsi
Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman P.O. Box 346, United Arab Emirates
Microtubule affinity regulating kinase 4 (MARK4) regulates the mechanism of microtubules by its ability to phosphorylate the microtubule-associated proteins (MAP’s). MARK4 is known for its major role in tau phosphorylation via phosphorylating Ser262 residue in the KXGS motif, which results in the detachment of tau from microtubule. In lieu of this vital role in tau pathology, a hallmark of Alzheimer’s disease (AD), MARK4 is a druggable target to treat AD and other neurodegenerative disorders (NDs). There is growing evidence that NDs and diabetes are connected with many pieces of literature demonstrating a high risk of developing AD in diabetic patients. Metformin (Mtf) has been a drug in use against type 2 diabetes mellitus (T2DM) for a long time; however, recent studies have established its therapeutic effect in neurodegenerative diseases (NDs), namely AD, Parkinson’s disease (PD) and amnestic mild cognitive impairment. In this study, we have explored the MARK4 inhibitory potential of Mtf, employing in silico and in vitro approaches. Molecular docking demonstrated that Mtf binds to MARK4 with a significant affinity of −6.9 kcal/mol forming interactions with binding pocket’s critical residues. Additionally, molecular dynamics (MD) simulation provided an atomistic insight into the binding of Mtf with MARK4. ATPase assay of MARK4 in the presence of Mtf shows that it inhibits MARK4 with an IC50 = 7.05 µM. The results of the fluorescence binding assay demonstrated significant binding of MARK4 with a binding constant of 0.6 × 106 M−1. The present study provides an additional axis towards the utilization of Mtf as MARK4 inhibitor targeting diabetes with NDs.
