title: Structure-based approaches in the design of GSK-3 selective inhibitors.
abstract: Glycogen Synthase Kinase-3 (GSK-3) is a serine/threonine kinase with varied number of actions in cellular signalling systems making it an emerging target for diseases such as diabetes mellitus, cancer, chronic inflammation, bipolar affective disorders and Alzheimer's disease. Various efforts have produced many potent small molecule inhibitors of GSK-3, which are being tested for modulation of glycogen metabolism, gene transcription, apoptosis and enhancement of insulin-stimulated glucose transport. Majority of the reported inhibitors show their inhibitory effects towards other phylogenetically related kinases also, like cyclin dependant kinases (CDKs). Thus it is important to develop inhibitors that can inhibit GSK-3 selectively. Rational approaches based on the knowledge of the receptor are best suited to address the selectivity problem. Several crystal structures of GSK-3beta with different ligands are being reported. These are providing the necessary clues regarding the interaction in the ligand binding domain. Several molecular docking efforts are being taken up to identify the clues for enhancing selectivity towards GSK-3. In this review we present current efforts and future opportunities in designing selective GSK-3 inhibitors.
authors: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar (Mohali) - 160 062, Punjab, India.
authors: Dhilon S
authors: DS
authors: Patel
authors: Nigus
authors: N
authors: Dessalew
authors: Pansy
authors: P
authors: Iqbal
authors: Prasad V
authors: PV
authors: Bharatam
mesh_terms: D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology; D008301:Maleimides / Q000378:metabolism / Q000494:pharmacology; D015394:Molecular Structure
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D000071679:Glycogen Synthase Kinase 3 beta; D051357:Cyclin-Dependent Kinase 2; D038362:Glycogen Synthase Kinase 3; C027185:indirubin