3D-QSAR Assisted Design of Novel 7-Deazapurine Derivatives as TNNI3K Kinase Inhibitors Using Molecular Docking and Molecular Dynamics Simulation

Abstract

Background: Cardiac troponin I-interacting kinase (TNNI3K) is a cardiac-specific kinase that belongs to MAPKKK family. It is a dual-function kinase with tyrosine and serine/threonine kinase activity. Over-expression of TNNI3K results in various cardiovascular diseases such as cardiomyopathy, ischemia/reperfusion injury, heart failure, etc. Since, it is a cardiac-specific kinase and expressed only in heart tissue, it is an ideal molecular target to treat cardiac diseases. The main objective of the work is to study and understand the structure-activity relationship of the reported deazapurine derivatives and to use the 3D-QSAR and docking results to design potent and novel TNNI3K inhibitors of this series. Methods: In the present study, we have used molecular docking 3D QSAR, and molecular dynamics simulation to understand the structure-activity correlation of reported TNNI3K inhibitors and to design novel compounds of deazapurine derivatives with increased activity. Results: Both CoMFA (q2=0.669, NOC=5, r2=0.944) and CoMSIA (q2=0.783, NOC=5, r2=0.965) have resulted in satisfactory models. The models were validated using external test set, Leave-out- Five, bootstrapping, progressive scrambling, and rm2 metrics calculations. The validation procedures showed the developed models were robust and reliable. The docking results and the contour maps analysis helped in the better understanding of the structure-activity relationship. Conclusion: This is the first report on 3D-QSAR modeling studies of TNNI3K inhibitors. Both docking and MD results were consistent and showed good correlation with the previous experimental data. Based on the information obtained from contour maps, 31 novel TNNI3K inhibitors were designed. These designed compounds showed higher activity than the existing dataset compounds.