Human serotine transporter (hSERT) is one of the most effective drug targets, and its allosteric modulators (e.g., escitalopram) are the next-generation medication for psychiatric disorders. Yet, the molecular mechanism underlying the allosteric modulation of hSERT remains elusive. 

A recent study applied conventional (cMD) and steered (SMD) molecular dynamics simulation strategies to investigate this molecular mechanism from distinct perspectives. 

First, cMD simulations showed that escitaloprams binding to hSERTs allosteric site simultaneously enhanced its binding to the orthosteric site. Further, SMD simulation recognized that the occupation of hSERTs allosteric site by escitalopram could also block its dissociation from the orthosteric site. Finally, after comparing the simulated structures of two hSERT–escitalopram complexes with and without allosteric modulation, the study identified a new conformational coupling between an extracellular (Arg104-Glu494) and an intracellular (Lys490-Glu494) salt bridge. 

 This study investigated the mechanism underlying the allosteric modulation of hSERT by combining two MD simulation strategies, which could facilitate our understanding of the allosteric modulations of hSERT and other clinically important therapeutic targets.

 This study explains how the antidepressant Escitalopram causes the allosteric modulation of hSERT, which further help alleviate symptoms of depression.

Xue W, Fu T, Deng S., et al., Molecular Mechanism for the Allosteric Inhibition of the Human Serotonin Transporter by Antidepressant Escitalopram. ACS Chem. Neurosci. 2022, 13, 3, 340–351