Molecular Modeling Studies of Triazolyl Thiophenes As CDK۵/P۲۵ inhHibitors Using ۳D-QSAR and Molecular Docking

Three-dimensional quantitative structure-activity relationship (۳D-QSAR) techniques are useful methods for ligand-based drug design by correlating physicochemical descriptors from a set of related compounds to their known molecular activity or molecular property values. A novel clubbed triazolyl thiophene series of cdk۵/p۲۵ inhibitors were selected to establish ۳D-QSAR models using Comparative molecular field analysis (CoMFA) and Comparative molecular similarity indices analysis (CoMSIA) methods. The optimum CoMFA and CoMSIA models obtained, were statistically significant with cross-validated correlation coefficients r۲cv (q۲) of ۰.۵۳۹ and ۰.۵۵۸, and conventional correlation coefficients (r۲) of ۰.۹۸۰ and ۰.۹۶۷, respectively. A training set containing ۸۸ molecules and a test set containing ۲۴ molecules served to establish the QSAR models. Independent test set validated the external predictive power of both models with predicted correlation coefficients (r۲pred) ۰.۹۶۸ and ۰.۹۴۵ for CoMFA and CoMSIA, respectively. Molecular docking was applied to explore the binding mode between the ligand and the receptor. The information obtained from molecular modeling studies may be helpful to design novel CDK۵/P۲۵ inhibitors with desired activity.

Keywords:

۳D-QSAR , molecular docking , Cdk۵/Pp۲۵ Inhibitors , triazolyl thiophene , Alzheimer disease