{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T19:35:04Z","timestamp":1790796904280,"version":"4.1.0"},"reference-count":36,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,21]],"date-time":"2022-07-21T00:00:00Z","timestamp":1658361600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Institutional Fund Projects","award":["IFPDP-31-22"],"award-info":[{"award-number":["IFPDP-31-22"]}]},{"DOI":"10.13039\/501100004054","name":"King Abdulaziz University","doi-asserted-by":"crossref","award":["IFPDP-31-22"],"award-info":[{"award-number":["IFPDP-31-22"]}],"id":[{"id":"10.13039\/501100004054","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Molecules"],"abstract":"<jats:p>Microtubule affinity regulating kinase 4 (MARK4) regulates the mechanism of microtubules by its ability to phosphorylate the microtubule-associated proteins (MAP\u2019s). 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\u2019s 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\u2019s 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 \u22126.9 kcal\/mol forming interactions with binding pocket\u2019s 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 \u00b5M. The results of the fluorescence binding assay demonstrated significant binding of MARK4 with a binding constant of 0.6 \u00d7 106 M\u22121. The present study provides an additional axis towards the utilization of Mtf as MARK4 inhibitor targeting diabetes with NDs.<\/jats:p>","DOI":"10.3390\/molecules27144652","type":"journal-article","created":{"date-parts":[[2022,7,21]],"date-time":"2022-07-21T22:38:50Z","timestamp":1658443130000},"page":"4652","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Inhibition of Microtubule Affinity Regulating Kinase 4 by Metformin: Exploring the Neuroprotective Potential of Antidiabetic Drug through Spectroscopic and Computational Approaches"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9820-2078","authenticated-orcid":false,"given":"Ghulam","family":"Ashraf","sequence":"first","affiliation":[{"name":"Department of Medical Laboratory Sciences, College of Health Sciences, and Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debarati","family":"DasGupta","sequence":"additional","affiliation":[{"name":"College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2843-169X","authenticated-orcid":false,"given":"Mohammad","family":"Alam","sequence":"additional","affiliation":[{"name":"Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia"},{"name":"Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3053-7912","authenticated-orcid":false,"given":"Saleh","family":"Baeesa","sequence":"additional","affiliation":[{"name":"Division of Neurosurgery, College of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9411-3609","authenticated-orcid":false,"given":"Badrah","family":"Alghamdi","sequence":"additional","affiliation":[{"name":"Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia"},{"name":"Department of Physiology, The Neuroscience Research Unit, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Firoz","family":"Anwar","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thamer","family":"Alqurashi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, King Abdul-Aziz University, Rabigh 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharaf","family":"Sharaf","sequence":"additional","affiliation":[{"name":"Pharmaceutical Chemistry Department, College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia"},{"name":"Clinical Research Administration, Executive Administration of Research and Innovation, King Abdullah Medical City in Holy Capital, Makkah 24246, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2984-9262","authenticated-orcid":false,"given":"Waleed","family":"Al Abdulmonem","sequence":"additional","affiliation":[{"name":"Department of Pathology, College of Medicine, Qassim University, P.O. Box 6655, Buraydah 51452, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5216-2277","authenticated-orcid":false,"given":"Mohammed","family":"Alyousef","sequence":"additional","affiliation":[{"name":"Division of Neurosurgery, College of Medicine, King Abdulaziz University Hospital, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0151-8309","authenticated-orcid":false,"given":"Fahad","family":"Alhumaydhi","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 52571, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7055-7056","authenticated-orcid":false,"given":"Anas","family":"Shamsi","sequence":"additional","affiliation":[{"name":"Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman P.O. Box 346, United Arab Emirates"},{"name":"Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5695","DOI":"10.2174\/1381612811319320005","article-title":"Hyperglycemia-induced oxidative stress and its role in diabetes mellitus related cardiovascular diseases","volume":"19","author":"Prioletta","year":"2013","journal-title":"Curr. Pharm. Des."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1902\/annals.2001.6.1.91","article-title":"The relationship between periodontal diseases and diabetes: An overview","volume":"6","author":"Soskolne","year":"2001","journal-title":"Ann. 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