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

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  • Sid Topiol, 3D 2drug LLC
  • ,
  • Benny Bang-Andersen, Lundbeck Res Denmark
  • ,
  • Connie Sanchez
  • Per Plenge, Univ Copenhagen, University of Copenhagen, Fac Hlth & Med Sci, Dept Neurosci & Pharmacol
  • ,
  • Claus J. Loland, Univ Copenhagen, University of Copenhagen, Fac Hlth & Med Sci, Dept Neurosci & Pharmacol
  • ,
  • Karsten Juhl, Lundbeck Res Denmark
  • ,
  • Krestian Larsen, Lundbeck Res Denmark
  • ,
  • Peter Bregnedal, Lundbeck Res Denmark
  • ,
  • Klaus P. Bogeso, Lundbeck Res Denmark

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. (C) 2016 Elsevier Ltd. All rights reserved.

Original languageEnglish
JournalBioorganic & Medicinal Chemistry Letters
Volume27
Issue3
Pages (from-to)470-478
Number of pages9
ISSN0960-894X
DOIs
Publication statusPublished - 1 Feb 2017

    Research areas

  • Structure-based drug design, Computer-aided drug discovery, Docking, X-ray structure, SERT, DAT, LeuT, HUMAN SEROTONIN TRANSPORTER, BINDING-SITE, DOPAMINE TRANSPORTER, NEUROTRANSMITTER TRANSPORTERS, BACTERIAL HOMOLOG, UPTAKE INHIBITORS, 5-HT TRANSPORTER, IN-VIVO, ESCITALOPRAM, ANTIDEPRESSANTS

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