Molecular Docking and 3D-QSAR Studies on 7-azaindole Derivatives as Inhibitors of Trk A: A Strategic Design in Novel Anticancer Agents

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, respectively. 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.