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Identification of novel serotonin transporter compounds by virtual screening.

  • Author(s): Gabrielsen, Mari
  • Kurczab, Rafał
  • Siwek, Agata
  • Wolak, Małgorzata
  • Ravna, Aina W
  • Kristiansen, Kurt
  • Kufareva, Irina
  • Abagyan, Ruben
  • Nowak, Gabriel
  • Chilmonczyk, Zdzisław
  • Sylte, Ingebrigt
  • Bojarski, Andrzej J
  • et al.

Published Web Location

https://doi.org/10.1021/ci400742s
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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