Discovery of novel-scaffold monoamine transporter ligands via in silico screening with the S1 pocket of the serotonin transporter
| Autor: | Laura M. Geffert, Benedict J. Kolber, Jeffry D. Madura, Christopher K. Surratt, Tammy L. Nolan |
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| Rok vydání: | 2014 |
| Předmět: |
Models
Molecular Computational chemistry Physiology Cognitive Neuroscience In silico Biology Pharmacology Ligands Biochemistry Mice Serotonin Agents Animals Humans Computer Simulation Serotonin transporter Serotonin Plasma Membrane Transport Proteins Virtual screening Norepinephrine Plasma Membrane Transport Proteins Monoamine transporter Dose-Response Relationship Drug Transporter Cell Biology General Medicine virtual screening Antidepressive Agents 3. Good health Monoamine neurotransmitter biology.protein Antidepressant antidepressant drug PubChem neurotransmitter transporter Research Article |
| Zdroj: | ACS Chemical Neuroscience |
| ISSN: | 1948-7193 |
| Popis: | Discovery of new inhibitors of the plasmalemmal monoamine transporters (MATs) continues to provide pharmacotherapeutic options for depression, addiction, attention deficit disorders, psychosis, narcolepsy, and Parkinson’s disease. The windfall of high-resolution MAT structural information afforded by X-ray crystallography has enabled the construction of credible computational models. Elucidation of lead compounds, creation of compound structure–activity series, and pharmacologic testing are staggering expenses that could be reduced by using a MAT computational model for virtual screening (VS) of structural libraries containing millions of compounds. Here, VS of the PubChem small molecule structural database using the S1 (primary substrate) ligand pocket of a serotonin transporter homology model yielded 19 prominent “hit” compounds. In vitro pharmacology of these VS hits revealed four structurally unique MAT substrate uptake inhibitors with high nanomolar affinity at one or more of the three MATs. In vivo characterization of three of these hits revealed significant activity in a mouse model of acute depression at doses that did not elicit untoward locomotor effects. This constitutes the first report of MAT inhibitor discovery using exclusively the primary substrate pocket as a VS tool. Novel-scaffold MAT inhibitors offer hope of new medications that lack the many classic adverse effects of existing antidepressant drugs. |
| Databáze: | OpenAIRE |
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