Investigation of the structure requirement for 5-HT 6 binding affinity of arylsulfonyl derivatives: A computational study

Abstract

5-HT 6 receptor has been implicated in a series of diseases including anxiety, depression, schizophrenia and cognitive dysfunctions. 5-HT 6 ligands have been reported to play a significant role in the treatment for central nervous system (CNS) diseases. Presently, a large series of 223 5-HT 6 ligands were studied using a combinational method by 3D-QSAR, molecular docking and molecular dynamics calculations for further improvement of potency. The optimal 3D models exhibit satisfying statistical results with r 2ncv, q 2 values of 0.85 and 0.50 for CoMFA, 0.81 and 0.53 for CoMSIA, respectively. Their predictive powers were validated by external test set, showing r 2pred of 0.71 and 0.76. The contour maps also provide a visual representation of contributions of steric, electrostatic, hydrophobic and hydrogen bond fields as well as the prospective binding models. In addition, the agreement between 3D-QSAR, molecular docking and molecular dynamics simulation proves the rationality of the developed models. These results, we hope, may be helpful in designing novel and potential 5-HT 6 ligands. © 2011 by the authors; licensee MDPI, Basel, Switzerland.