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Mortensen OV, Kortagere S. Designing modulators of monoamine transporters using virtual screening techniques. Front Pharmacol. 2015;6:223doi: 10.3389/fphar.2015.00223.
Mortensen, O. V., & Kortagere, S. (2015). Designing modulators of monoamine transporters using virtual screening techniques. Frontiers in pharmacology, 6223. https://doi.org/10.3389/fphar.2015.00223
Mortensen, Ole V, and Kortagere, Sandhya. "Designing modulators of monoamine transporters using virtual screening techniques." Frontiers in pharmacology vol. 6 (2015): 223. doi: https://doi.org/10.3389/fphar.2015.00223
Mortensen OV, Kortagere S. Designing modulators of monoamine transporters using virtual screening techniques. Front Pharmacol. 2015 Sep 29;6:223. doi: 10.3389/fphar.2015.00223. eCollection 2015. PMID: 26483692; PMCID: PMC4586420.
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Front Pharmacol. 2015 Sep 29;6:223. doi: 10.3389/fphar.2015.00223. eCollection 2015.

Designing modulators of monoamine transporters using virtual screening techniques.

Frontiers in pharmacology

Ole V Mortensen, Sandhya Kortagere

Affiliations

  1. Department of Pharmacology and Physiology, Drexel University College of Medicine , Philadelphia, PA, USA.
  2. Department of Microbiology and Immunology, Drexel University College of Medicine , Philadelphia, PA, USA.

PMID: 26483692 PMCID: PMC4586420 DOI: 10.3389/fphar.2015.00223

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.

Keywords: dopamine transporter; hybrid structure based screening; modeling and simulations; monoamine transporters; norepinephrine transporter; serotonin transporter; virtual screening

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