Drug design of new 5-HT6 antagonists: a QSAR study of arylsulfonamide derivatives


Several studies underscore that the 5-hydroxytryptamine subtype 6 (5-HT6) receptor is intrinsically related to the onset of Alzheimer’s disease and its blocking significantly improve the learning and memory processes. In this manuscript, we apply quantitative structure-activity relationship (QSAR) techniques to a series of potential arylsulfonamide-derived 5-HT6 receptor antagonists aiming to design new anti-AD ligands. In order to describe physicochemical properties of the compounds, a plethora of descriptor types was calculated, and then selected by statistical techniques to build models that relate the chemical structure to antagonist activity of these studied ligands. Thereafter, structural variations were performed on the C15, C25, and C47 compounds by analyzing the steric and electrostatic fields as well as 2D maps. At last, the new compounds were submitted to the constructed QSAR models which presented promising results. It is noteworthy that the C4704 compound exhibited the highest biological activity value, surpassing even the values of the compounds used in the construction of the model. In conclusion, the robustness of the model allowed to confidently predict the biological activity values of the designed compounds.

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This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior–Brasil (CAPES) (Finance Code 001), FAPESP (2016/10118-0,2018/06680-7), and CNPq. The research carried out using the computational resources of the Center for Mathematical Sciences Applied to Industry (CeMEAI) is funded by FAPESP (grant 2013/07375-0).

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Correspondence to Albérico B. F. da Silva.

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da Silva, A.P., de Angelo, R.M., de Paula, H. et al. Drug design of new 5-HT6 antagonists: a QSAR study of arylsulfonamide derivatives. Struct Chem 31, 1585–1597 (2020). https://doi.org/10.1007/s11224-020-01513-z

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  • QSAR
  • PLS
  • CoMFA
  • Drug-design
  • Alzheimer