title: 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.
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.
authors.affiliation: 3D-2drug, LLC, P.O. Box 184, Fair Lawn, NJ, USA. Electronic address: sid.topiol@3D-2drug.com.
authors.forename: Sid
authors.initials: S
authors.lastname: Topiol
authors.affiliation: Lundbeck Research, H. Lundbeck A/S, Copenhagen, Denmark.
authors.forename: Benny
authors.initials: B
authors.lastname: Bang-Andersen
authors.affiliation: Translational Neuropsychiatry Unit, Clinical Medicine, Aarhus University, Denmark.
authors.forename: Connie
authors.initials: C
authors.lastname: Sanchez
authors.affiliation: Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Plenge
authors.affiliation: Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Claus J
authors.initials: CJ
authors.lastname: Loland
authors.affiliation: Lundbeck Research, H. Lundbeck A/S, Copenhagen, Denmark.
authors.forename: Karsten
authors.initials: K
authors.lastname: Juhl
authors.affiliation: Lundbeck Research, H. Lundbeck A/S, Copenhagen, Denmark.
authors.forename: Krestian
authors.initials: K
authors.lastname: Larsen
authors.affiliation: Formerly of Lundbeck Research, H. Lundbeck A/S, Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Bregnedal
authors.affiliation: Formerly of Lundbeck Research, H. Lundbeck A/S, Copenhagen, Denmark.
authors.forename: Klaus P
authors.initials: KP
authors.lastname: Bøgesø
mesh_terms: D000495:Allosteric Site; D001665:Binding Sites; D015283:Citalopram / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D056004:Molecular Dynamics Simulation; D017434:Protein Structure, Tertiary; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D015283:Citalopram; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Computer-aided drug discovery; DAT; Docking; LeuT; SERT; Structure-based drug design; X-ray structure