Computational studies of TGF-βRI (ALK-5) inhibitors: Analysis of the binding interactions between ligand–receptor using 2D and 3D techniques

ALK-5 (Activin-Like Kinase 5) is a biological receptor involved in a variety of pathological processes such as cancer and fibrosis. ALK-5 receptor propagates an intracellular signaling that forms a protein complex capable of reaching the nucleus and modulating the gene transcription. In the present study, comparative molecular field analysis (CoMFA) and hologram quantitative structure–activity relationship (HQSAR) studies were conducted on a series of potent ALK-5 inhibitors. Significant correlation coefficients (CoMFA, r2 = 0.99 and q2 = 0.85; HQSAR, r2 = 0.92 and q2 = 0.72) were obtained, indicating the predictive potential of the 2D and 3D models for untested compounds. The models were then used to predict the potency of a test set, and the predicted values from the HQSAR and CoMFA models were in good agreement with the experimental results. The final QSAR models, along with the information obtained from 3D (steric and electrostatic) contour maps and 2D contribution maps, can be useful for the design of novel bioactive ligands.

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