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.