Identification and in vitro evaluation of new leads as selective and competitive glycogen synthase kinase-3 beta inhibitors through ligand and structure based drug design

作者：Darshit B S; Balaji B; Rani P; Ramanathan M^*

来源：Journal of Molecular Graphics and Modelling, 2014, 53: 31-47.

DOI：10.1016/j.jmgm.2014.06.013

• Structure based drug design (SBDD)
• Ligand based drug design (LBDD)
• Virtual screening
• Glycogen synthase kinase-3 beta (GSK-3 beta)
• Cyclin dependent kinase 5/p25 (CDK5/p25)
• Kinase assay

Glycogen synthase kinase-3 beta elicits multi-functional effects on intracellular signaling pathways, thereby making the kinase a therapeutic target in multiple pathologies. Hence, it is important to selectively inhibit GSK-3 beta over structurally and biologically similar targets, such as CDK5. The current study was designed to identify and evaluate novel ATP-competitive GSK-3 beta inhibitors. The study was designed to identify new leads by ligand based drug design, structure based drug design and in vitro evaluation. The best validated pharmacophore model (AADRRR) identified using LBDD was derived from a dataset of 135 molecules. There were 357 primary hits within the SPECS database using this pharmacophore model. A SBDD approach to the GSK-3 beta and CDK5 proteins was applied to all primary hits, and 5 selective inhibitors were identified for GSK-3 beta. GSK-3 beta and CDK5 in vitro kinase inhibition assays were performed with these molecules to confirm their selectivity for GSK-3 beta. The molecules showed IC50 values ranging from 0.825 mu M to 1.116 mu M and were 23- to 57-fold selective for GSK-3 beta. Of all the molecules, molecule 3 had the lowest IC50 value of 0.825 mu M. Our research identified molecules possessing benzothiophene, isoquinoline, thiazolidinedione imidazo-isoquinoline and quinazolinone scaffolds. Potency of these molecules may be due to H-bond interaction with backbone residues of Val135, Asp133 and side chain interaction with Tyr134. Selectivity over CDK5 may be due to side chain interactions with Asp200, backbone of Val61, ionic interaction with Lys60 and pi-cationic interaction with Arg141. These selective molecules were also exhibited small atom hydrophobicity and pi-bond interaction with water molecule.

• 出版日期2014-9