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      Identification of Novel Serotonin Transporter Compounds by Virtual Screening

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          Abstract

          The serotonin (5-hydroxytryptamine, 5-HT) transporter (SERT) plays an essential role in the termination of serotonergic neurotransmission by removing 5-HT from the synaptic cleft into the presynaptic neuron. It is also of pharmacological importance being targeted by antidepressants and psychostimulant drugs. Here, five commercial databases containing approximately 3.24 million drug-like compounds have been screened using a combination of two-dimensional (2D) fingerprint-based and three-dimensional (3D) pharmacophore-based screening and flexible docking into multiple conformations of the binding pocket detected in an outward-open SERT homology model. Following virtual screening (VS), selected compounds were evaluated using in vitro screening and full binding assays and an in silico hit-to-lead (H2L) screening was performed to obtain analogues of the identified compounds. Using this multistep VS/H2L approach, 74 active compounds, 46 of which had K i values of ≤1000 nM, belonging to 16 structural classes, have been identified, and multiple compounds share no structural resemblance with known SERT binders.

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          Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters.

          Atsuko Yamashita, Satinder K. Singh, Toshimitsu Kawate … (2005)
          Na+/Cl--dependent transporters terminate synaptic transmission by using electrochemical gradients to drive the uptake of neurotransmitters, including the biogenic amines, from the synapse to the cytoplasm of neurons and glia. These transporters are the targets of therapeutic and illicit compounds, and their dysfunction has been implicated in multiple diseases of the nervous system. Here we present the crystal structure of a bacterial homologue of these transporters from Aquifex aeolicus, in complex with its substrate, leucine, and two sodium ions. The protein core consists of the first ten of twelve transmembrane segments, with segments 1-5 related to 6-10 by a pseudo-two-fold axis in the membrane plane. Leucine and the sodium ions are bound within the protein core, halfway across the membrane bilayer, in an occluded site devoid of water. The leucine and ion binding sites are defined by partially unwound transmembrane helices, with main-chain atoms and helix dipoles having key roles in substrate and ion binding. The structure reveals the architecture of this important class of transporter, illuminates the determinants of substrate binding and ion selectivity, and defines the external and internal gates.
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            TCDB: the Transporter Classification Database for membrane transport protein analyses and information

            Milton Saier, Can Tran, Ravi Barabote (2005)
            The Transporter Classification Database (TCDB) is a web accessible, curated, relational database containing sequence, classification, structural, functional and evolutionary information about transport systems from a variety of living organisms. TCDB is a curated repository for factual information compiled from >10 000 references, encompassing ∼3000 representative transporters and putative transporters, classified into >400 families. The transporter classification (TC) system is an International Union of Biochemistry and Molecular Biology approved system of nomenclature for transport protein classification. TCDB is freely accessible at . The web interface provides several different methods for accessing the data, including step-by-step access to hierarchical classification, direct search by sequence or TC number and full-text searching. The functional ontology that underlies the database structure facilitates powerful query searches that yield valuable data in a quick and easy way. The TCDB website also offers several tools specifically designed for analyzing the unique characteristics of transport proteins. TCDB not only provides curated information and a tool for classifying newly identified membrane proteins, but also serves as a genome transporter-annotation tool.
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              X-ray structure of dopamine transporter elucidates antidepressant mechanism.

              Aravind Penmatsa, Kevin Wang, Eric Gouaux (2013)
              Antidepressants targeting Na(+)/Cl(-)-coupled neurotransmitter uptake define a key therapeutic strategy to treat clinical depression and neuropathic pain. However, identifying the molecular interactions that underlie the pharmacological activity of these transport inhibitors, and thus the mechanism by which the inhibitors lead to increased synaptic neurotransmitter levels, has proven elusive. Here we present the crystal structure of the Drosophila melanogaster dopamine transporter at 3.0 Å resolution bound to the tricyclic antidepressant nortriptyline. The transporter is locked in an outward-open conformation with nortriptyline wedged between transmembrane helices 1, 3, 6 and 8, blocking the transporter from binding substrate and from isomerizing to an inward-facing conformation. Although the overall structure of the dopamine transporter is similar to that of its prokaryotic relative LeuT, there are multiple distinctions, including a kink in transmembrane helix 12 halfway across the membrane bilayer, a latch-like carboxy-terminal helix that caps the cytoplasmic gate, and a cholesterol molecule wedged within a groove formed by transmembrane helices 1a, 5 and 7. Taken together, the dopamine transporter structure reveals the molecular basis for antidepressant action on sodium-coupled neurotransmitter symporters and elucidates critical elements of eukaryotic transporter structure and modulation by lipids, thus expanding our understanding of the mechanism and regulation of neurotransmitter uptake at chemical synapses.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Chem Inf Model
                Journal ID (iso-abbrev): J Chem Inf Model
                Journal ID (publisher-id): ci
                Journal ID (coden): jcisd8
                Title: Journal of Chemical Information and Modeling
                Publisher: American Chemical Society
                ISSN (Print): 1549-9596
                ISSN (Electronic): 1549-960X
                Publication date PMC-release: 12 February 2015
                Publication date (Electronic): 12 February 2014
                Publication date (Print): 24 March 2014
                Volume: 54
                Issue: 3
                Pages: 933-943
                Affiliations
                [† ]Medical Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, UiT, The Arctic University of Norway , 9037 Tromsø, Norway
                [‡ ]Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences , 12 Smętna Street, 31-343 Kraków, Poland
                [§ ]Department of Pharmacobiology, Jagiellonian University Medical College , Medyczna 9, 30-688 Kraków, Poland
                [∇ ]Skaggs School of Pharmacy and Pharmaceutical Sciences , 9500 Gilman Drive, MC 0747 La Jolla, California 92093-0747, United States
                [⊥ ]Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences , 12 Smętna Street, 31-343 Kraków, Poland
                [∥ ]National Medicines Institute , 30/34 Chełmska Street, 00-725 Warsaw, Poland
                Author notes
                [* ]Tel.: +48126623365. E-mail: bojarski@ 123456if-pan.krakow.pl .
                Article
                DOI: 10.1021/ci400742s
                PMC ID: 3982395
                PubMed ID: 24521202
                SO-VID: de7b575c-3d20-4065-9f93-e969c9f2cffd
                Copyright © Copyright © 2014 American Chemical Society
                History
                Date received : 12 December 2013
                Funding
                National Institutes of Health, United States
                Categories
                Subject: Article
                Custom metadata
                document-id-old-9 ci400742s
                document-id-new-14 ci-2013-00742s
                ccc-price

                ScienceOpen disciplines: Computational chemistry & Modeling
                Data availability:
                ScienceOpen disciplines: Computational chemistry & Modeling

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