Background: Trk A kinase plays a crucial role in the cell cycle events including
survival, proliferation and differentiation in normal and neoplastic neuronal cells. Thus, it has been
proved as an important target for cancer pharmaceutical.
Methods: A series of twenty-three Trk A inhibitors containing 7-azaindole scaffold were studied
based on a combination of two computational techniques, the Three-Dimensional Quantitative
Structure Activity Relationship (3D-QSAR) following by molecular docking. The Comparative
Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA)
were developed using eighteen molecules having pIC50 ranging from 5.777 to 2.499. The best
generated CoMFA and CoMSIA models show conventional determination coefficients R2 of 0.98
and 0.98 as well as their leave-one-out cross-validation determination coefficients Q2 of 0.51 and
0.64, respectively. The predictive ability of those models was evaluated by the external validation
using a test set of five compounds with predicted determination coefficients R2
test of 0.74 and 0.80,
Results: The most and the least active compounds from the dataset were docked into the active site
of the protein (PDB ID: 4aoj) to interpret those results obtained from 3D-QSAR models and to
elucidate the binding mode between this type of compounds and the Trk A protein.
Conclusion: These satisfactory results are not offered help only to understand the binding mode of
substituted azaindoles into this type of targets, but provide information to design new potent Trk A
inhibitors. According to the good concordance between the CoMFA/CoMSIA contour maps and
docking results, the obtained information was explored to design novel molecules.