RESUMEN

The recent publication of X-ray structures of SERT includes structures with the potent antidepressant S-Citalopram (S-Cit). Earlier predictions of ligand binding at both a primary (S1) and an allosteric modulator site (S2), were confirmed. We provide herein examples of a series of Citalopram analogs, showing distinct structure-activity relationship (SAR) at both sites that is independent of the SAR at the other site. Analogs with a higher affinity and selectivity than benchmark R-Citalopram (R-Cit) for the S2 versus the S1 site were identified. We deploy structural and computational analyses to explain this SAR and demonstrate the potential utility of the newly emerging X-ray structures within the neurotransmitter:sodium Symporter family for drug design.

Asunto(s)

Citalopram/análogos & derivados , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Sitio Alostérico , Sitios de Unión , Citalopram/síntesis química , Citalopram/metabolismo , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Simulación de Dinámica Molecular , Estructura Terciaria de Proteína , Proteínas de Transporte de Serotonina en la Membrana Plasmática/química , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/metabolismo , Estereoisomerismo , Relación Estructura-Actividad