Kinetics and Molecular Docking Study of an Anti-diabetic Drug Glimepiride as Acetylcholinesterase Inhibitor: Implication for Alzheimer’s Disease-Diabetes Dual Therapy
- 635 Downloads
At the present time, treatment of two most common degenerative disorders of elderly population i.e., Type 2 Diabetes Mellitus (T2DM) and Alzheimer’s disease (AD) is a major concern worldwide. As there are several evidences that proved strong linkages between these two disorders, the idea of using dual therapeutic agent for both the diseases might be considered as a good initiative. Earlier reports have revealed that oral anti-diabetic drugs such as peroxisome proliferator activated receptor γ (PPARγ) agonists (thiazolidinediones) when used in T2DM patients suffering from AD showed improved memory and cognition. However, the underlying mechanism still needs to be deciphered. Therefore, the present study was carried out to find whether glimepiride, an oral antidiabetic drug which is a PPARγ agonist could inhibit the activity of acetylcholine esterase (AChE) enzyme. Actually, AChE inhibitors seize the breakdown of acetylcholine which forms the main therapeutic strategy for AD. Here, glimepiride showed dose dependent inhibitory activity against AChE enzyme with IC50 value of 235 μM. Kinetic analysis showed competitive inhibition, which was verified by in silico docking studies. Glimepiride was found to interact with AChE enzyme at the same locus as that of substrate acetylcholine iodide (AChI). Interestingly, amino acid residues, Q71, Y72, V73, D74, W86, N87, Y124, S125, W286, F295, F297, Y337, F338 and Y341 of AChE were found to be common for ‘glimepiride–AChE interaction’ as well as ‘AChI–AChE interaction’. Thus the present computational and kinetics study concludes that glimepiride and other thiazolidinediones derivatives could form the basis of future dual therapy against diabetes associated neurological disorders.
KeywordsAlzheimer’s disease Acetylcholinesterase Acetylcholine iodide Competitive inhibition Glimepiride Type 2 Diabetes Mellitus
Shaikh S is supported by INSPIRE grant from Department of Science & Technology, New Delhi, India (Grant Number: IF130056), which is sincerely acknowledged. Shazi Shakil thanks all of the staff of Center of Innovation in Personalized Medicine (CIPM), King Abdulaziz University, Saudi Arabia for continued support.
Compliance with Ethical Standards
Conflict of interest
The authors declare that there is no conflict of interests regarding the publication of this paper.
- 8.Davis KL, Thai LJ, Gamzu ER, Davis CS, Woolson RF, Gracon SI, Drachman DA, Schneider LS, Whitehouse PJ, Hoover TM (1992) A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer’s disease, The Tacrine Collaborative Study Group. N Engl J Med 327:1253–1259CrossRefPubMedGoogle Scholar
- 9.Xu SS, Gao ZX, Weng Z, Du ZM, Xu WA, Yang JS (1995) Efficacy of tablet huperzine-A on memory, cognition, and behavior in Alzheimer’s disease. Acta Pharmacol Sin 16:391–395Google Scholar
- 10.AD 2000 Collaborative Group (2000) Long-term donepezil treatmentin 565 patients with Alzheimer’s disease (AD2000): randomized double-blind trial. Lancet 363:2105–2115Google Scholar
- 25.Rizvi SMD, Shakil S, Biswas D, Shakil S, Shaikh S, Bagga P, Kamal MA (2014) Invokana (Canagliflozin) as a dual inhibitor of acetylcholinesterase and sodium glucose co-transporter 2: advancement in Alzheimer’s disease-diabetes type 2 linkage via an Enzoinformatics Study. CNS Neurol Disord Drug Targets 13:447–451CrossRefPubMedGoogle Scholar
- 36.Gutiérrez M, Arévaloa B, Martínezb G, Valdésa F, Vallejosc G, Carmonad U, Martine AS (2015) Synthesis, molecular docking and design of Tetra hydroquinolines as acetylcholinesterase inhibitors. J Chem Pharm Res 7:351–358Google Scholar
- 37.Watson GS, Cholerton BA, Reger MA, Baker LD, Plymate SR, Asthana S, Fishel MA, Kulstad JJ, Green PS, Cook DG, Kahn SE, Keeling ML, Craft S (2005) Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. Am J Geriatr Psychiatry 13:950–958PubMedGoogle Scholar
- 39.Shaikh S, Ahmad SS, Ansari MA, Shakil S, Rizvi SMD, Shakil S, Tabrez S, Akhtar S, Kamal MA (2014) Prediction of comparative inhibition efficiency for a novel natural ligand, Galangin against human brain Acetylcholinesterase, butyrylcholinesterase and 5-Lipoxygenase: a Neuroinformatics study. CNS Neurol Disord Drug Targets 13:452–459CrossRefPubMedGoogle Scholar
- 42.Shaikh S, Zainab T, Shakil S, Rizvi SMD (2015) A neuroinformatics study to compare inhibition efficiency of three natural ligands (Fawcettimine, Cernuine and Lycodine) against Human Brain Acetylcholinesterase. Network Comput Neural Syst 26:26–35Google Scholar
- 43.Alam A, Shaikh S, Ahmad SS, Ansari MA, Shakil S, Rizvi SMD, Shakil S, Imran M, Haneef M, Abuzenadah AM, Kamal MA (2014) Molecular interaction of human brain acetylcholinesterase with a natural inhibitor Huperzine-B. An Enzoinformatics approach. CNS Neurol Disord Drug Targets 13:487–490CrossRefPubMedGoogle Scholar