title: Molecular Interaction of Anti-Diabetic Drugs With Acetylcholinesterase and Sodium Glucose Co-Transporter 2.
abstract: Type 2 Diabetes Mellitus (T2DM) and Alzheimer's disease (AD) are the two disorders which are known to share pertinent pathological and therapeutic links. Sodium glucose co-transporter-2 (SGLT2) and Acetylcholinesterase (AChE) are established inhibition targets for T2DM and AD treatments, respectively. Reports suggest that anti-diabetic drugs could be used for AD treatment also. The present study used molecular docking by Autodock4.2 using our "Click-By-Click"-protocol, Ligplot1.4.3 and "change in accessible surface area (ΔASA)-calculations" to investigate the binding of two investigational anti-diabetic drugs, Ertugliflozin and Sotagliflozin to an established target (SGLT2) and a research target (human brain AChE). Sotagliflozin appeared more promising for SGLT2 as well as AChE-inhibition with reference to ΔG and Ki values in comparison to Ertugliflozin. The ΔG and Ki values for "Sotagliflozin:AChE-binding" were -7.16 kcal/mol and 5.6 μM, respectively while the same were found to be -8.47 kcal/mol and 0.62 μM, respectively for its interaction with SGLT2. Furthermore, "Sotagliflozin:SGLT2-interaction" was subjected to (un)binding simulation analyses by "Molecular-Motion-Algorithms." This information is significant as the exact binding mode, interacting amino acid residues and simulation results for the said interaction have not been described yet. Also no X-ray crystal is available for the same. Finally, the results described herein indicate that Sotagliflozin could have an edge over Ertugliflozin for treatment of Type 2 diabetes. Future design of drugs based on Sotagliflozin scaffolds for treatment of Type 2 and/or Type 3 diabetes are highly recommended. As these drugs are still in late phases of clinical trials, the results described herein appear timely. J. Cell. Biochem. 118: 3855-3865, 2017. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Shazi
authors.identifier: 0000-0003-4075-9153
authors.initials: S
authors.lastname: Shakil
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D000465:Algorithms; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry*; D006027:Glycosides / Q000737:chemistry*; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry*; D062105:Molecular Docking Simulation; D051297:Sodium-Glucose Transporter 2 / Q000737:chemistry*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D006027:Glycosides; D007004:Hypoglycemic Agents; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; C575681:(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol; C570288:ertugliflozin; D000110:Acetylcholinesterase
keywords: ERTUGLIFLOZIN; MOLECULAR DOCKING; SIMULATION; SODIUM GLUCOSE CO-TRANSPORTERS; SOTAGLIFLOZIN; TYPE 2 DIABETES; TYPE 3 DIABETES