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Monoamine Transporter Structure, Function, Dynamics, and Drug Discovery: A Computational Perspective

  • Review Article
  • Theme: New Paradigms in Pharmaceutical Sciences: In Silico Drug Discovery
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Abstract

With the breakthrough crystallization of the bacterial leucine transporter protein LeuT, the first available X-ray structure for the neurotransmitter/sodium symporter family, development of 3-D computational models is suddenly essential for structure–function studies on the plasmalemmal monoamine transporters (MATs). LeuT-based MAT models have been used to guide elucidation of substrate and inhibitor binding pockets, and molecular dynamics simulations using these models are providing insight into conformations involved in the substrate translocation cycle. With credible MAT models finally in hand, structure-based virtual screening for novel ligands is yielding lead compounds toward the development of new medications for psychostimulant dependence, attention deficit hyperactivity, depression, anxiety, schizophrenia, and other disorders associated with dopamine, norepinephrine, or serotonin dysregulation.

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Abbreviations

DAT:

dopamine transporter

GABA:

gamma-aminobutyric acid

MAT:

monoamine transporter

MD:

molecular dynamics

MSA:

multiple sequence alignment

NET:

norepinephrine transporter

NRI:

norepinephrine reuptake inhibitor

NSS:

neurotransmitter/sodium symporter

SERT:

serotonin transporter

SSRI:

selective serotonin reuptake inhibitor

TCA:

tricyclic antidepressant

TM:

transmembrane

VS:

virtual screening

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ACKNOWLEDGMENTS

This work was supported by the National Institute on Drug Abuse under award DA026530 (C.K.S.) and the National Institutes of Health, National Science Foundation, Department of Defense, and the U.S. Department of Education under awards DA27806 (J.D.M.), CHE-1005145(REU/ASSURE), CHE-0723109(MRI), and P116Z080180 (J.D.M.).

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Authors and Affiliations

  1. Department of Chemistry and Biochemistry, Center for Computational Sciences, Duquesne University, Pittsburgh, Pennsylvania, USA

    Sankar Manepalli, Jeffry D. Madura & Tammy L. Nolan

  2. Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University, Pittsburgh, Pennsylvania, USA

    Christopher K. Surratt & Tammy L. Nolan

  3. Duquesne University, 600 Forbes Ave, 411 Mellon Hall, Pittsburgh, Pennsylvania, 15282, USA

    Tammy L. Nolan

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  1. Sankar Manepalli
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  2. Christopher K. Surratt
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Correspondence to Tammy L. Nolan.

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Guest Editor: Xiang-Qun Xie

Electronic Supplementary Material

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Supplementary Figure 1

Beuming et al ( 24). primary amino acid sequence alignment of LeuT Aa with the human MATs. N- and C-terminal tails were not used for model building and are not shown. Amino acid residue position (red numbers) is indicated at the beginning and end of each row; LeuT residue increments of 10 (blue numbers) are indicated above the row; gaps in alignment are shown as dots. Identical (blue) and similar (yellow) aligned residues are highlighted. Secondary structural features for transmembrane domains (TM), intracellular loops (IL), extracellular loops (EL) and beta-strands (B) are displayed above the sequence rows. Charged residues of the extracellular (blue spheres) and intracellular (orange spheres) gates and residues of the hydrophobic extracellular gate (red stars) are noted below the sequence rows. (JPEG 2383 kb)

High resolution image file (EPS 594 kb)

Supplementary Figure 2

SERT (green) embedded within a POPE lipid bilayer (van der Waals spheres). Hydrocarbon tails (gray) of the phospholipids are oriented toward the center of the cell membrane, arranged tail-to-tail; the polar head groups containing phosphorous (pink), oxygen (red) and nitrogen (blue) atoms are oriented toward the hydrophilic borders of the membrane. The translocation pore is defined by the primary (S1, yellow) and secondary (S2, cyan) substrate binding pockets and are displayed as surfaces. Ions and water molecules are hidden for the sake of clarity, as is the front portion of the lipid bilayer. (JPEG 2390 kb)

High resolution image file (EPS 760 kb)

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Manepalli, S., Surratt, C.K., Madura, J.D. et al. Monoamine Transporter Structure, Function, Dynamics, and Drug Discovery: A Computational Perspective. AAPS J 14, 820–831 (2012). https://doi.org/10.1208/s12248-012-9391-0

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