title: Identification of novel serotonin transporter compounds by virtual screening.
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.
authors: Medical Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, UiT, The Arctic University of Norway , 9037 Tromsø, Norway.
authors: Mari
authors: M
authors: Gabrielsen
authors: Rafał
authors: R
authors: Kurczab
authors: Agata
authors: A
authors: Siwek
authors: Małgorzata
authors: M
authors: Wolak
authors: Aina W
authors: AW
authors: Ravna
authors: Kurt
authors: K
authors: Kristiansen
authors: Irina
authors: I
authors: Kufareva
authors: Ruben
authors: R
authors: Abagyan
authors: Gabriel
authors: G
authors: Nowak
authors: Zdzisław
authors: Z
authors: Chilmonczyk
authors: Ingebrigt
authors: I
authors: Sylte
authors: Andrzej J
authors: AJ
authors: Bojarski
mesh_terms: D001665:Binding Sites; D062313:Databases, Pharmaceutical; D055808:Drug Discovery; D006801:Humans; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011619:Psychotropic Drugs / Q000737:chemistry* / Q000494:pharmacology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D011619:Psychotropic Drugs; D050486:Serotonin Plasma Membrane Transport Proteins