A rational approach to selective pharmacophore designing: an innovative strategy for specific recognition of Gsk3β.
We propose a novel cheminformatics approach that combines structure and ligand-based design to identify target-specific pharmacophores with well-defined exclusion ability. Our strategy includes the prediction of selective interactions, developing structure, and knowledge-based selective pharmacophore models, followed by database screening and molecular docking. This unique strategy was employed in addressing the off-target toxicity of Gsk3β and CDKs. The connections of Gsk3β in eukaryotic cell apoptosis and the extensive potency of Gsk3β inhibitors to block cell death have made it a potential drug-discovery target for many grievous human disorders. Gsk3β is phylogenetically very closely related to the CDKs, such as CDK1 and CDK2, which are suggested to be the off-target proteins of Gsk3β inhibitors. Here, we have employed novel computational approaches in designing the ligand candidates that are potentially inhibitory against Gsk3β, with well-defined the exclusion ability to CDKs. A structure-ligand -based selective pharmacophore was modeled. This model was used to retrieve molecules from the zinc database. The hits retrieved were further screened by molecular docking and protein-ligand interaction fingerprints. Based on these results, four molecules were predicted as selective Gsk3β antagonists. It is anticipated that this unique approach can be extended to investigate any protein-ligand specificity.
Bioinformatics Centre, School of Biotechnology, National Institute of Technology, Calicut 673601, India.
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Pradeep
G K
GK
Rajanikant
D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D048088:Informatics / Q000379:methods*; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D013379:Substrate Specificity
D008024:Ligands; D047428:Protein Kinase Inhibitors; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3