PMID- 35889524 OWN - NLM STAT- MEDLINE DCOM- 20220728 LR - 20230321 IS - 1420-3049 (Electronic) IS - 1420-3049 (Linking) VI - 27 IP - 14 DP - 2022 Jul 21 TI - Inhibition of Microtubule Affinity Regulating Kinase 4 by Metformin: Exploring the Neuroprotective Potential of Antidiabetic Drug through Spectroscopic and Computational Approaches. LID - 10.3390/molecules27144652 [doi] LID - 4652 AB - 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 Ser(262) 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 IC(50) = 7.05 microM. The results of the fluorescence binding assay demonstrated significant binding of MARK4 with a binding constant of 0.6 x 10(6) M(-1). The present study provides an additional axis towards the utilization of Mtf as MARK4 inhibitor targeting diabetes with NDs. FAU - Ashraf, Ghulam Md AU - Ashraf GM AUID- ORCID: 0000-0002-9820-2078 AD - Department of Medical Laboratory Sciences, College of Health Sciences, and Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates FAU - DasGupta, Debarati AU - DasGupta D AD - College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109, USA FAU - Alam, Mohammad Zubair AU - Alam MZ AD - Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia AD - Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia FAU - Baeesa, Saleh S AU - Baeesa SS AUID- ORCID: 0000-0002-3053-7912 AD - Division of Neurosurgery, College of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia FAU - Alghamdi, Badrah S AU - Alghamdi BS AUID- ORCID: 0000-0002-9411-3609 AD - Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia AD - Department of Physiology, The Neuroscience Research Unit, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia FAU - Anwar, Firoz AU - Anwar F AD - Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia FAU - Alqurashi, Thamer M A AU - Alqurashi TMA AD - Department of Pharmacology, Faculty of Medicine, King Abdul-Aziz University, Rabigh 21589, Saudi Arabia FAU - Sharaf, Sharaf E AU - Sharaf SE AD - Pharmaceutical Chemistry Department, College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia AD - Clinical Research Administration, Executive Administration of Research and Innovation, King Abdullah Medical City in Holy Capital, Makkah 24246, Saudi Arabia FAU - Al Abdulmonem, Waleed AU - Al Abdulmonem W AUID- ORCID: 0000-0003-2984-9262 AD - Department of Pathology, College of Medicine, Qassim University, P.O. Box 6655, Buraydah 51452, Saudi Arabia FAU - Alyousef, Mohammed A AU - Alyousef MA AUID- ORCID: 0000-0002-5216-2277 AD - Division of Neurosurgery, College of Medicine, King Abdulaziz University Hospital, Jeddah 21589, Saudi Arabia FAU - Alhumaydhi, Fahad A AU - Alhumaydhi FA AUID- ORCID: 0000-0002-0151-8309 AD - Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 52571, Saudi Arabia FAU - Shamsi, Anas AU - Shamsi A AUID- ORCID: 0000-0001-7055-7056 AD - Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman P.O. Box 346, United Arab Emirates AD - Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India LA - eng GR - IFPRC-196-141-2020/King Abdulaziz University/ PT - Journal Article DEP - 20220721 PL - Switzerland TA - Molecules JT - Molecules (Basel, Switzerland) JID - 100964009 RN - 0 (Hypoglycemic Agents) RN - 9100L32L2N (Metformin) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) SB - IM EIN - Molecules. 2023 Jan 06;28(2):. PMID: 36677971 MH - *Alzheimer Disease/drug therapy/metabolism MH - *Diabetes Mellitus, Type 2/drug therapy/metabolism MH - Humans MH - Hypoglycemic Agents/metabolism/pharmacology MH - *Metformin/pharmacology MH - Microtubules/metabolism MH - Molecular Docking Simulation MH - Protein Binding MH - Protein Serine-Threonine Kinases PMC - PMC9320910 OTO - NOTNLM OT - Alzheimer's disease OT - MARK4 OT - MD simulation OT - drug discovery OT - drug repurposing OT - molecular docking OT - type 2 diabetes mellitus OT - virtual screening COIS- All authors declare that they have no conflict of interest. EDAT- 2022/07/28 06:00 MHDA- 2022/07/29 06:00 PMCR- 2022/07/21 CRDT- 2022/07/27 01:35 PHST- 2022/06/24 00:00 [received] PHST- 2022/07/08 00:00 [revised] PHST- 2022/07/14 00:00 [accepted] PHST- 2022/07/27 01:35 [entrez] PHST- 2022/07/28 06:00 [pubmed] PHST- 2022/07/29 06:00 [medline] PHST- 2022/07/21 00:00 [pmc-release] AID - molecules27144652 [pii] AID - molecules-27-04652 [pii] AID - 10.3390/molecules27144652 [doi] PST - epublish SO - Molecules. 2022 Jul 21;27(14):4652. doi: 10.3390/molecules27144652.