Quantitative Structure-Activity Relationship Studies: Understanding the Mechanism of Tyrosine Kinase Inhibition

Objective: To investigate the various physicochemical descriptors employed towards biological activity of tyrosine kinase inhibitors. Background: In oncology, kinase domain has emerged as an important pharmacological target. The receptor tyrosine kinases on deregulation (i.e. over expression, chromosomal translocation, gene amplication, mutation) contribute towards development of cancer and thus it has been emerged as potential target in oncology. Method: The available 2D/3D-QSAR methodologies like Hansch analysis, CoMFA, CoMSIA provide the models to correlate biological activity with their 2D/3D descriptors. The identified electrostatic, steric, H-bond, hydrophobic interaction energies involved in ligand-receptor interactions were analyzed. Results: The QSAR models derived for some of the well reported and evaluated tyrosine kinase inhibitors like benzimidazole, pyrido[2,3-d]pyrimidine, quniazolines, quinolines, pyrrolo-pyrimidines, biphenyl amide-based, phenylaminopyrimidine-based, indolinones, and 1,4-dihydroindeno[1,2-c]pyrazole derivatives have found to be useful to investigate the mechanism of tyrosine kinase inhibition. Conclusion: The validated and tested QSAR and 3D-QSAR models for different chemical classes of tyrosine kinase inhibitors have acceptable predictive power. Application: The compiled data on some of the available derived 2D/3D-QSAR models as well as contributing descriptors has utility in understanding structure-activity relationship studies in respect to various endpoints within the chemical series.