Molecular Photoswitches Regulating the Activity of the Human Serotonin Transporter

Abstract

Serotonin is an essential mediator regulating diverse neural processes, and its deregulation is related to debilitating neurological diseases. In particular, the human serotonin transporter (hSERT) is fundamental in completing the synaptic neural cycle by allowing the reuptake of serotonin. Its inhibition is particularly attractive, especially as a pharmacological target against depressive syndrome. Here, we analyze, by using long-range molecular dynamic simulations, the behavior of a molecular photoswitch whose cis- and trans-isomers inhibit the hSERT differently. In particular, we evidence the structural and molecular basis behind the higher inhibiting capacity of the cis-isomer, which blocks more efficiently the hSERT conformational cycle leading to serotonin uptake. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/558680v1_ufig1.gif" ALT="Figure 1"> View larger version (98K): org.highwire.dtl.DTLVardef@75d82dorg.highwire.dtl.DTLVardef@c38d43org.highwire.dtl.DTLVardef@6f3c90org.highwire.dtl.DTLVardef@f12399_HPS_FORMAT_FIGEXP M_FIG C_FIG