title: Discovery of novel-scaffold monoamine transporter ligands via in silico screening with the S1 pocket of the serotonin transporter.
abstract: 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.
authors.affiliation: Division of Pharmaceutical Sciences, Mylan School of Pharmacy, ‡Departments of Chemistry and Biochemistry, Center for Computational Sciences, and §Department of Biological Sciences, Duquesne University , 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, United States.
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Nolan
authors.forename: Laura M
authors.initials: LM
authors.lastname: Geffert
authors.forename: Benedict J
authors.initials: BJ
authors.lastname: Kolber
authors.forename: Jeffry D
authors.initials: JD
authors.lastname: Madura
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Surratt
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism; D018490:Serotonin Agents / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000928:Antidepressive Agents; D008024:Ligands; D050484:Norepinephrine Plasma Membrane Transport Proteins; D018490:Serotonin Agents; D050486:Serotonin Plasma Membrane Transport Proteins
keywords: Computational chemistry; antidepressant drug; neurotransmitter transporter; virtual screening