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Molecular dynamics of conformation-specific dopamine transporter-inhibitor complexes.
J Mol Graph Model. 2017 09; 76:143-151.JM

Abstract

The recreational psychostimulant cocaine inhibits dopamine reuptake from the synapse, resulting in excessive stimulation of postsynaptic dopamine receptors in brain areas associated with reward and addiction. Cocaine binds to and stabilizes the outward- (extracellular-) facing conformation of the dopamine transporter (DAT) protein, while the low abuse potential DAT inhibitor benztropine prefers the inward- (cytoplasmic-) facing conformation. A correlation has been previously postulated between psychostimulant abuse potential and preference for the outward-facing DAT conformation. The 3β-aryltropane cocaine analogs LX10 and LX11, however, differ only in stereochemistry and share a preference for the outward-facing DAT, yet are reported to vary widely in abuse potential in an animal model. In search of the molecular basis for DAT conformation preference, complexes of cocaine, benztropine, LX10 or LX11 bound to each DAT conformation were subjected to 100ns of all-atom molecular dynamics simulation. Results were consistent with previous findings from cysteine accessibility assays used to assess an inhibitor's DAT conformation preference. The respective 2β- and 2α-substituted phenyltropanes of LX10 and LX11 interacted with hydrophobic regions of the DAT S1 binding site that were inaccessible to cocaine. Solvent accessibility measurements also revealed subtle differences in inhibitor positioning within a given DAT conformation. This work serves to advance our understanding of the conformational selectivity of DAT inhibitors and suggests that MD may be useful in antipsychostimulant therapeutic design.

Authors+Show Affiliations

Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, PA 15282, United States.Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, United States. Electronic address: surratt@duq.edu.Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, PA 15282, United States.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

28734204

Citation

Jean, Bernandie, et al. "Molecular Dynamics of Conformation-specific Dopamine Transporter-inhibitor Complexes." Journal of Molecular Graphics & Modelling, vol. 76, 2017, pp. 143-151.
Jean B, Surratt CK, Madura JD. Molecular dynamics of conformation-specific dopamine transporter-inhibitor complexes. J Mol Graph Model. 2017;76:143-151.
Jean, B., Surratt, C. K., & Madura, J. D. (2017). Molecular dynamics of conformation-specific dopamine transporter-inhibitor complexes. Journal of Molecular Graphics & Modelling, 76, 143-151. https://doi.org/10.1016/j.jmgm.2017.07.003
Jean B, Surratt CK, Madura JD. Molecular Dynamics of Conformation-specific Dopamine Transporter-inhibitor Complexes. J Mol Graph Model. 2017;76:143-151. PubMed PMID: 28734204.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular dynamics of conformation-specific dopamine transporter-inhibitor complexes. AU - Jean,Bernandie, AU - Surratt,Christopher K, AU - Madura,Jeffry D, Y1 - 2017/07/11/ PY - 2017/03/22/received PY - 2017/07/03/revised PY - 2017/07/04/accepted PY - 2017/7/25/pubmed PY - 2018/5/3/medline PY - 2017/7/23/entrez KW - Cocaine KW - Dopamine KW - Inhibitor-stabilized conformation KW - Molecular dynamics KW - Neurotransmitter transporter KW - Psychostimulant SP - 143 EP - 151 JF - Journal of molecular graphics & modelling JO - J. Mol. Graph. Model. VL - 76 N2 - The recreational psychostimulant cocaine inhibits dopamine reuptake from the synapse, resulting in excessive stimulation of postsynaptic dopamine receptors in brain areas associated with reward and addiction. Cocaine binds to and stabilizes the outward- (extracellular-) facing conformation of the dopamine transporter (DAT) protein, while the low abuse potential DAT inhibitor benztropine prefers the inward- (cytoplasmic-) facing conformation. A correlation has been previously postulated between psychostimulant abuse potential and preference for the outward-facing DAT conformation. The 3β-aryltropane cocaine analogs LX10 and LX11, however, differ only in stereochemistry and share a preference for the outward-facing DAT, yet are reported to vary widely in abuse potential in an animal model. In search of the molecular basis for DAT conformation preference, complexes of cocaine, benztropine, LX10 or LX11 bound to each DAT conformation were subjected to 100ns of all-atom molecular dynamics simulation. Results were consistent with previous findings from cysteine accessibility assays used to assess an inhibitor's DAT conformation preference. The respective 2β- and 2α-substituted phenyltropanes of LX10 and LX11 interacted with hydrophobic regions of the DAT S1 binding site that were inaccessible to cocaine. Solvent accessibility measurements also revealed subtle differences in inhibitor positioning within a given DAT conformation. This work serves to advance our understanding of the conformational selectivity of DAT inhibitors and suggests that MD may be useful in antipsychostimulant therapeutic design. SN - 1873-4243 UR - https://www.unboundmedicine.com/medline/citation/28734204/Molecular_dynamics_of_conformation_specific_dopamine_transporter_inhibitor_complexes_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1093-3263(17)30189-4 DB - PRIME DP - Unbound Medicine ER -