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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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| Authors: | Sid Topiol Benny Bang-Andersen Connie Sanchez Per Plenge Claus J Loland Karsten Juhl Krestian Larsen Peter Bregnedal Klaus P Bøgesø |
| Institution: | 1. 3D-2drug, LLC, P.O. Box 184, Fair Lawn, NJ, USA;2. Lundbeck Research, H. Lundbeck A/S, Copenhagen, Denmark;3. Translational Neuropsychiatry Unit, Clinical Medicine, Aarhus University, Denmark;4. Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark;5. Formerly of Lundbeck Research, H. Lundbeck A/S, Copenhagen, Denmark |
| 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: | SERT serotonin transporter DAT dopamine transporter NAT noradrenaline transporter NSS neurotransmitter:sodium symporter SSRI selective serotonin reuptake inhibitor TCA tricyclic antidepressant dDAT LeuT leucine transporter Structure-based drug design Computer-aided drug discovery Docking X-ray structure SERT DAT LeuT |
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