INSILICO STUDIES OF OXIME PRODRUG OF GLICLAZIDE AGAINST SULPHONYLUREA RECEPTORS (SUR 1)
Keywords:Insilico study, Oxime prodrug, Gliclazide, Sulphonylurea receptors
Objective: Objective of the study is to perform a molecular docking analysis of novel oxime prodrug of gliclazide against SUR1 receptor.
Methods: Sulfonylurea receptorsÂ (SUR) areÂ membrane proteinsÂ which are the molecular targets of theÂ sulfonylureaÂ class ofÂ anti-diabetic drugs whose mechanism of action is to promoteÂ insulin release fromÂ pancreaticÂ beta cells. Oxime prodrug of gliclazide a better soluble derivative of gliclazide is used for enhancement of bioavailability of gliclazide. Autodock 4.2 software was used for docking studies. Ligand 2D structures were drawn using ChemDraw Ultra 7.0. Binding sites, docking poses and interactions of the ligand with SUR1 receptors were studied by pymol software.
Results: The docking studies suggest that potential binding sites of oxime prodrug of gliclazide exhibiting all the major interactions such as hydrogen bonding, hydrophobic interaction and electrostatic interaction with GLU43, LEU11, LEU 40, ILE17 GLU 68, GLN72 residues of SUR1. The binding energy of complexes are also found to be minimal forming stable complexes.Conclusion: In silico study of oxime prodrug of gliclazide conforms, the binding of oxime prodrug of glicalzide with SUR1 receptors which effectively controls the release insulin to regulate plasma glucose concentrations. Hence, the oxime prodrug of gliclazide could be a potent anti-diabetic target molecule which may be worth for further in vitro and in vivostudies.
Lengauer T, Rarey M. Computational methods for biomolecular docking. Curr Opin Struct Biol 1996;6:402â€“6.
Izadi S, Aguilar B, Onufriev AV. Protein-ligand electrostatic binding free energies from explicit and implicit solvation. J Chem Theory Comput 2015;11:4450â€“9.
Sharma NK, Jha KK. Molecular docking: an overview. J Adv Sci Res 2010;1:67-72.
Ferreira LG, Dos Santos RN, Oliva G, Andricopulo AD. Molecular docking and structure-based drug design strategies. Molecules 2015;20:13384-421.
American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2009;32:S62â€“S67.
Donley VR, Hiskett EK, Kidder AC, Schermerhorn T. ATP-sensitive potassium channel (KATP channel) expression in the normal canine pancreas and in canine insulinomas. BMC Vet Res 2005;1:8.
Aguilar-Bryan L, Nichols CG, Wechsler SW, Clement JP, Boyd AE, Gonzalez G, et al. Cloning of the Î² cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science 1995;268:423â€“6.
Atwal KS, Grove GJ, Lodge NJ, Normandin DE, Traeger SC, Sleph PG, et al. Binding of ATP-sensitive potassium channel (KATP) openers to cardiac membranes: correlation of binding affinities with cardioprotective and smooth muscle relaxing potencies. J Med Chem 1988;41:271â€“5.
Barrett-Jolley R, Mcpherson GA. Characterization of KATP channels in intact mammalian skeletal muscle fibres. Br J Pharmacol 1998;123:1103â€“10.
Irons BK, Minze MG. Drug treatment of type 2 diabetes mellitus in patients for whom metformin is contraindicated. Diabetes Metab Syndr Obes: Targets Ther 2014;7:15â€“24.
Kalra S, Aamir AH, Abbas Raza, Das AK, Azad Khan AK, Shrestha D, et al. Place of sulfonylureas in the management of type 2 diabetes mellitus in South Asia: a consensus statement. Indian J Endocrinol Metab 2015;19:577-96.
Vijayaraj S, Anitha S, Omshanthi B, Sampath Kumar KP. Synthesis and characterization of novel oxime prodrug of gliclizide. Asian J Chem 2014;26:6989-92.
Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 2009;30:2785-91.