A high quality homology model for the human dopamine transporter validated for drug design purposes.

07:00 EST 5th February 2019 | BioPortfolio

Summary of "A high quality homology model for the human dopamine transporter validated for drug design purposes."

The human dopamine transporter (hDAT) plays many vital functions within the central nervous system and is thus targeted by many pharmaceutical agents. Dopamine-related therapies are in current development for individuals with dopamine-related disorders including depression, Parkinson's disease, and psychostimulant addictions such as cocaine abuse. Yet, most efforts to develop new dopamine therapies are within costly structure activity relationship studies. Through structure based drug design techniques, the binding site of hDAT can be utilized to develop novel selective and potent dopamine therapies at reduced costs. However, no structural models of hDAT specifically validated for rational drug design purposes currently exists. Here, using the Drosophila dopamine transporter as a template, a homology model for the human dopamine transporter was developed and validated. The model was able to reproduce experimental binding modes with great accuracy, was able to rank inhibitors in the correct order of increasing potency with an R value of 0.81 for the test set, and it also out performed other published hDAT models. Thus, the model can be used reliably in structure based drug design projects. This article is protected by copyright. All rights reserved.


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Name: Chemical biology & drug design
ISSN: 1747-0285


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Medical and Biotech [MESH] Definitions

A high-affinity, low capacity system y+ amino acid transporter with strong similarity to CATIONIC AMINO ACID TRANSPORTER 1. The two isoforms of the protein, CAT-2A and CAT-2B, exist due to alternative mRNA splicing. The transporter has specificity for the transport of ARGININE; LYSINE; and ORNITHINE.

Sodium chloride-dependent neurotransmitter symporters located primarily on the PLASMA MEMBRANE of dopaminergic neurons. They remove DOPAMINE from the EXTRACELLULAR SPACE by high affinity reuptake into PRESYNAPTIC TERMINALS and are the target of DOPAMINE UPTAKE INHIBITORS.

Cell-surface proteins that bind dopamine with high affinity and trigger intracellular changes influencing the behavior of cells.

Organic cation transporter consisting of twelve transmembrane domains and expressed primarily in the kidney. It transports a wide range of metabolites, drugs, and neurotransmitters from the blood to the KIDNEY TUBULES, including DOPAMINE; SEROTONIN; CHOLINE; and CISPLATIN.

A subtype of dopamine D2 receptors that has high affinity for the antipsychotic CLOZAPINE.

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