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ACS Chem Neurosci. 2017 Aug 16;8(8):1735-1746. doi: 10.1021/acschemneuro.7b00094. Epub 2017 May 4.

The Isomeric Preference of an Atypical Dopamine Transporter Inhibitor Contributes to Its Selection of the Transporter Conformation.

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Computational Chemistry and Molecular Biophysics Unit, Molecular Targets and Medications Discovery Branch, NIH/NIDA/IRP, Baltimore, Maryland 21224, United States.
Computational Molecular Biology group, Institute for Mathematics, Freie Universität Berlin , Arnimallee 6, 14195 Berlin, Germany.
Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University , New York, New York 10065, United States.
Molecular Neuropharmacology Group, Department of Neuroscience and Pharmacology, The Faculty of Health Sciences, The Panum Institute, University of Copenhagen , DK-2200 Copenhagen, Denmark.


Cocaine, a widely abused psychostimulant, inhibits the dopamine transporter (DAT) by trapping the protein in an outward-open conformation, whereas atypical DAT inhibitors such as benztropine have low abuse liability and prefer less outward-open conformations. Here, we use a spectrum of computational modeling and simulation approaches to obtain the underlying molecular mechanism in atomistic detail. Interestingly, our quantum mechanical calculations and molecular dynamics (MD) simulations suggest that a benztropine derivative JHW007 prefers a different stereoisomeric conformation of tropane in binding to DAT compared to that of a cocaine derivative, CFT. To further investigate the different inhibition mechanisms of DAT, we carried out MD simulations in combination with Markov state modeling analysis of wild-type and Y156F DAT in the absence of any ligand or the presence of CFT or JHW007. Our results indicate that the Y156F mutation and CFT shift the conformational equilibrium toward an outward-open conformation, whereas JHW007 prefers an inward-occluded conformation. Our findings reveal the mechanistic details of DAT inhibition by JHW007 at the atomistic level, which provide clues for rational design of atypical inhibitors.


Cocaine; Markov state model analysis; atypical inhibitor; dopamine transporter; molecular dynamics

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