A high-quality homology model for the human dopamine transporter validated for drug design purposes
| Autor: | Matthew C. Castellana, Jon E. Sprague, Tarek M. Mahfouz, Andrea Castellar Montes |
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| Rok vydání: | 2018 |
| Předmět: |
Drug
Computer science media_common.quotation_subject Drug design Computational biology Nortriptyline 01 natural sciences Biochemistry Inhibitory Concentration 50 Dopamine Drug Discovery medicine Animals Drosophila Proteins Humans Homology modeling media_common Dopamine transporter Pharmacology Dopamine Plasma Membrane Transport Proteins Binding Sites biology 010405 organic chemistry Addiction Organic Chemistry 0104 chemical sciences Protein Structure Tertiary Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Drug Design biology.protein Molecular Medicine Drosophila Cocaine abuse medicine.drug |
| Zdroj: | Chemical biologydrug design. 93(5) |
| ISSN: | 1747-0285 |
| Popis: | 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 exist. Here, using the Drosophila dopamine transporter as a template, a homology model for the hDAT 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 R2 value of 0.81 for the test set, and it also outperformed other published hDAT models. Thus, the model can be used reliably in structure-based drug design projects. |
| Databáze: | OpenAIRE |
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