X-ray structure based evaluation of analogs of citalopram: Compounds with increased affinity and selectivity compared with R-citalopram for the allosteric site (S2) on hSERT

Bioorg Med Chem Lett. 2017 Feb 1;27(3):470-478. doi: 10.1016/j.bmcl.2016.12.037. Epub 2016 Dec 21.

Abstract

The recent publication of X-ray structures of SERT includes structures with the potent antidepressant S-Citalopram (S-Cit). Earlier predictions of ligand binding at both a primary (S1) and an allosteric modulator site (S2), were confirmed. We provide herein examples of a series of Citalopram analogs, showing distinct structure-activity relationship (SAR) at both sites that is independent of the SAR at the other site. Analogs with a higher affinity and selectivity than benchmark R-Citalopram (R-Cit) for the S2 versus the S1 site were identified. We deploy structural and computational analyses to explain this SAR and demonstrate the potential utility of the newly emerging X-ray structures within the neurotransmitter:sodium Symporter family for drug design.

Keywords: Computer-aided drug discovery; DAT; Docking; LeuT; SERT; Structure-based drug design; X-ray structure.

MeSH terms

  • Allosteric Site
  • Binding Sites
  • Citalopram / analogs & derivatives*
  • Citalopram / chemical synthesis
  • Citalopram / metabolism
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Inhibitory Concentration 50
  • Molecular Dynamics Simulation
  • Protein Structure, Tertiary
  • Selective Serotonin Reuptake Inhibitors / chemical synthesis
  • Selective Serotonin Reuptake Inhibitors / chemistry
  • Selective Serotonin Reuptake Inhibitors / metabolism
  • Serotonin Plasma Membrane Transport Proteins / chemistry
  • Serotonin Plasma Membrane Transport Proteins / metabolism*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • Citalopram