In silico prediction of inhibitory effects of pyrazol-5-one and indazole derivatives on GSK3β kinase enzyme

Glycogen synthase kinase-3 beta (GSK3β) plays an important role in a diverse number of regulatory pathways by phosphorylation of several different cellular targets and its inhibitors have been evaluated as promising drug candidates. In this work, 192 3-aryl-4-(arylhydrazono)-1H-pyrazol-5-one analogs (AHP) and indazoles (ID) derivatives possessing selective binding affinity for GSK3β kinase were studied using the 3D-QSAR/CoMFA/CoMSIA methodologies. The obtained CoMFA/CoMSIA models exhibit both good internal and external predictive abilities, i.e., Rcv2=0.551,Rpred2=0.698 for AHP derivatives and Rcv2=0.511,Rpred2=0.791 for ID analogs. Of paramount interest is the observation derived from the combination of molecular dynamics and molecular docking studies that Val135 and Asp133 are responsible for the binding recognition for AHP molecules, while residues Val135 and Pro136 are mainly involved in the specific ligand–kinase interactions for ID analogs. The developed models are seeking to be helpful for the rational design of novel potent GSK3β inhibitors.

► GSK3β is regarded as novel therapeutic targets for many diseases.
► 3D-QSAR, molecular docking and MD simulation were performed on two different series of GSK3β inhibitors.
► H-bond properties are found to play crucial roles for the activity.
► The obtained results can help in the development of novel potent GSK3β inhibitors.