Identification of novel serotonin transporter compounds by virtual screening

J Chem Inf Model. 2014 Mar 24;54(3):933-43. doi: 10.1021/ci400742s. Epub 2014 Feb 26.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Databases, Pharmaceutical
  • Drug Discovery
  • Humans
  • Molecular Docking Simulation
  • Protein Binding
  • Psychotropic Drugs / chemistry*
  • Psychotropic Drugs / pharmacology*
  • Serotonin Plasma Membrane Transport Proteins / chemistry
  • Serotonin Plasma Membrane Transport Proteins / metabolism*

Substances

  • Psychotropic Drugs
  • Serotonin Plasma Membrane Transport Proteins