Designing modulators of monoamine transporters using virtual screening techniques

Abstract

The plasma-membrane monoamine transporters (MATs), including the serotonin (SERT), norepinephrine (NET) and dopamine (DAT) transporters, serve a pivotal role in limiting monoamine-mediated neurotransmission through the reuptake of their respective monoamine neurotransmitters. The transporters are the main target of clinically used psychostimulants and antidepressants. Despite the availability of several potent and selective MAT substrates and inhibitors the continuing need for therapeutic drugs to treat brain disorders involving aberrant monoamine signaling provides a compelling reason to identify novel ways of targeting and modulating the MATs. Designing novel modulators of MAT function have been limited by the lack of three dimensional structure information of the individual MATs. However, crystal structures of LeuT, a bacterial homolog of MATs, in a substrate-bound occluded, substrate-free outward-open, and an apo inward-open state and also with competitive and non-competitive inhibitors have been determined. In addition, several structures of the Drosophila DAT have also been resolved. Together with computational modeling and experimental data gathered over the past decade, these structures have dramatically advanced our understanding of several aspects of SERT, NET, and DAT transporter function, including some of the molecular determinants of ligand interaction at orthosteric substrate and inhibitor binding pockets. In addition progress has been made in the understanding of how allosteric modulation of MAT function can be achieved. Here we will review all the efforts up to date that has been made through computational approaches employing structural models of MATs to design small molecule modulators to the orthosteric and allosteric sites using virtual screening techniques.

Mapping Cholesterol Interaction Sites on Serotonin Transporter through Coarse-Grained Molecular Dynamics

“…Furthermore, S2 site has been proposed as a symport effector in NSS [62, 63]. Together, these evidences led to addressing this pocket in the attempt to identify novel allosteric SERT inhibitors [64]. Similar implications were found for sub-site A2, which is associated to a cholesterol binding mode rotated of approximately 90° around Y495 towards EL6 and TM12 (Fig 4h).…”

Scaffold Repurposing of Nucleosides (Adenosine Receptor Agonists): Enhanced Activity at the Human Dopamine and Norepinephrine Sodium Symporters

“…Allosteric modulation of SERT is well validated structurally, 33 and that of NET has been described; for example, a peptide inhibitor was suggested to bind to the extracellular vestibule of the transporter. 35,36 …”

Overview of Monoamine Transporters

“…ATM7 was one of the ligands identified using this approach. It allosterically modulates the 5‐HT uptake as well as MDMA‐elicited reverse transport (Kortagere et al., ; Mortensen & Kortagere, ). The x‐ray crystal structure of hSERT with one molecule of escitalopram bound to the S1 site and another bound in the extracellular vestibule region provides direct evidence of the presence of an allosteric site in SERT (Coleman et al., ).…”