Design, synthesis and cytotoxic evaluation of a selective serotonin reuptake inhibitor (SSRI) by virtual screening

Autores organización

• Diana Milena Millan Cortes

  Autor

• 

  James Oswaldo Guevara Pulido

  Autor

Autores

• Jaramillo DN

Grupos de investigación

• Grupo de Investigación Básica y Traslacional (GIBAT)

  Investigador

  Rafael Antonio Guerrero Rojas

• Investigación en Química Aplicada INQA

  

  Investigador

  James Oswaldo Guevara Pulido

Resumen

Depression is one of the most common mental illnesses, affecting almost 300 million people. According to the WHO, depression is one of the world's leading causes of disability and morbidity. People with this illness require both psychological and pharmaceutical treatment because severe depressive episodes often result in suicide. Selective serotonin reuptake inhibitors (SSRI) are widely used antidepressants that target the human serotonin transporter (hSERT). The crystallization of hSERT and the experimental data available allows cost and time-efficient computational tools like virtual screening (VS) to be utilized in the development of therapeutic agents. Here, we synthesized, characterized, and evaluated the biological activity of a novel SSRI analog of paroxetine, rationally designed by applying an artificial neural network-based QSAR model and a molecular docking analysis on hSERT. The analog N-substituted 18a showed higher affinity for the transporter (-10.2 kcal/mol), lower Ki value (1.19 nM) and a safer toxicological profile than paroxetine and was synthesized with a 71% yield. The in vitro cytotoxicity of the analog was evaluated using human glioblastoma (U87 MG), human neuroblastoma (SH SY5Y) and murine fibroblast (L929) cell lines. Also, the hemolytic ability of the compound was assessed on human erythrocytes. Results showed that analog 18a did not exhibit cytotoxic activity on the cell lines used and has no hemolytic activity at any of the concentrations tested, whereas with paroxetine, hemolysis was observed at 2.3, 1.29 y 0.67 mM. Based on these results, it is possible to suggest that analog 18a could be a promising new SSRI candidate for the treatment of this illness. © 2023 The Author(s)

Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.

Keywords

• Animals; Antidepressive Agents; Humans; Mice; Molecular Docking Simulation; Paroxetine; Selective Serotonin Reuptake Inhibitors; Serotonin Plasma Membrane Transport Proteins; paroxetine; serotonin uptake inhibitor; antidepressant agent; paroxetine; serotonin transporter; serotonin uptake inhibitor; Article; artificial neural network; controlled study; depression; drug cytotoxicity; drug design; drug synthesis; erythrocyte; hemolysis; human; human cell; in vitro study; molecular docking; NCTC clone 929 cell line; quantitative structure activity relation; SH-SY5Y cell line; U-87MG-Luc cell line; animal; metabolism; mouse