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Journal article
Designing modulators of monoamine transporters using virtual screening techniques
Frontiers in pharmacology, v 6, pp 223-223
29 Sep 2015
PMID: 26483692
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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Details
- Title
- Designing modulators of monoamine transporters using virtual screening techniques
- Creators
- Ole V. Mortensen - Drexel UniversitySandhya Kortagere - Drexel University
- Publication Details
- Frontiers in pharmacology, v 6, pp 223-223
- Publisher
- Frontiers Media Sa
- Number of pages
- 8
- Grant note
- R01MH106912 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01MH106912 / NATIONAL INSTITUTE OF MENTAL HEALTH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology; Pharmacology and Physiology
- Web of Science ID
- WOS:000365621000001
- Scopus ID
- 2-s2.0-84944745977
- Other Identifier
- 991019168095104721
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- Web of Science research areas
- Pharmacology & Pharmacy