title: In silico-based combinatorial pharmacophore modelling and docking studies of GSK-3β and GK inhibitors of Hippophae.
abstract: Type 2 diabetes is an inevitably progressive disease, with irreversible beta cell failure. Glycogen synthase kinase and Glukokinase, two important enzymes with diverse biological actions in carbohydrate metabolism, are promising targets for developing novel antidiabetic drugs. A combinatorial structure-based molecular docking and pharmacophore modelling study was performed with the compounds of Hippophae salicifolia and H. rhamnoides as inhibitors. Docking with Discovery Studio 3.5 revealed that two compounds from H. salicifolia, viz Lutein D and an analogue of Zeaxanthin, and two compounds from H. rhamnoides, viz Isorhamnetin-3-rhamnoside and Isorhamnetin-7-glucoside, bind significantly to the GSK-3 beta receptor and play a role in its inhibition; whereas in the case of Glucokinase, only one compound from both the plants, i.e. vitamin C, had good binding characteristics capable of activation. The results help to understand the type of interactions that occur between the ligands and the receptors. Toxicity predictions revealed that none of the compounds had hepatotoxic effects and had good absorption as well as solubility characteristics. The compounds did not possess plasma protein-binding, crossing blood-brain barrier ability. Further, in vivo and in vitro studies need to be performed to prove that these compounds can be used effectively as antidiabetic drugs.
authors.affiliation: DBT-BIF Facility, Department of Biotechnology and Biochemistry, Maharani Lakshmi Ammanni College For Women, Malleswaram, Bangalore 560 012, India.
authors.forename: Sushil Kumar
authors.initials: SK
authors.lastname: Middha
authors.forename: Arvind Kumar
authors.initials: AK
authors.lastname: Goyal
authors.forename: Syed Ahmed
authors.initials: SA
authors.lastname: Faizan
authors.forename: Nethramurthy
authors.initials: N
authors.lastname: Sanghamitra
authors.forename: Bharat Chandra
authors.initials: BC
authors.lastname: Basistha
authors.forename: Talambedu
authors.initials: T
authors.lastname: Usha
mesh_terms: D001205:Ascorbic Acid / Q000737:chemistry; D020134:Catalytic Domain; D062126:Databases, Chemical; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry*; D005941:Glucokinase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D005960:Glucosides / Q000737:chemistry; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000071679:Glycogen Synthase Kinase 3 beta; D031281:Hippophae / Q000737:chemistry / Q000201:enzymology*; D007004:Hypoglycemic Agents / Q000737:chemistry*; D007700:Kinetics; D014975:Lutein / Q000737:chemistry; D062105:Molecular Docking Simulation; D011485:Protein Binding; D013816:Thermodynamics; D024341:Xanthophylls / Q000737:chemistry; D065146:Zeaxanthins
chemical_list: D004791:Enzyme Inhibitors; D005960:Glucosides; D007004:Hypoglycemic Agents; D024341:Xanthophylls; D065146:Zeaxanthins; D005941:Glucokinase; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D001205:Ascorbic Acid; D014975:Lutein