Molecular docking and three-dimensional quantitative structure-activity relationship studies on 5-HT6 receptor inhibitors and design of new compounds

CoMFA and CoMSIA methods were used to perform 3D quantitative structure-activity relationship (3D-QSAR) evaluation and molecular docking, of 5-HT6 receptor inhibitors. The CoMFA model performed on training set in biases of alignment with suitable statistical parameters (q2= 0.556, r2 = 0.836, F= 26.334, SEE=0.171). The best prediction for 5-HT6 receptor inhibitors was obtained by CoMFA (after focusing region) model with highest predictive ability (q2= 0.599, r2 = 0.857, F= 30.853, SEE=0.160) in biases of the same alignment. Using the same alignment, a consistent CoMSIA model was obtained (q2= 0.580, r2 = 0.752, F= 34.361, SEE=0.201) from the three combinations. To evaluate the prediction capability of the CoMFA and CoMSIA models, a test set of 9 compounds was used so that they could show the good predictive r2 values for CoMFA, CoMFA (after focusing region), and CoMSIA models, 0.554, 0.473, and 0.670, respectively. The obtained contour maps form models were used to identify the structural features responsible for the biological activity to design potent 5-HT6 receptor inhibitors. Molecular docking analysis along with the CoMSIA model could reveal the significant role of hydrophobic characteristics in increasing the inhibitors potency. Using the results, some new compounds were designed which showed the higher inhibitory activities as 5-HT6 receptor inhibitors.