The Isomeric Preference of an Atypical Dopamine Transporter Inhibitor Contributes to Its Selection of the Transporter Conformation
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The Isomeric Preference of an Atypical Dopamine Transporter Inhibitor Contributes to Its Selection of the Transporter Conformation. / Abramyan, Ara M.; Stolzenberg, Sebastian; Li, Zheng; Loland, Claus J.; Noe, Frank; Shi, Lei.
In: A C S Chemical Neuroscience, Vol. 8, No. 8, 2017, p. 1735-1746.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - The Isomeric Preference of an Atypical Dopamine Transporter Inhibitor Contributes to Its Selection of the Transporter Conformation
AU - Abramyan, Ara M.
AU - Stolzenberg, Sebastian
AU - Li, Zheng
AU - Loland, Claus J.
AU - Noe, Frank
AU - Shi, Lei
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Cocaine
KW - dopamine transporter
KW - atypical inhibitor
KW - molecular dynamics
KW - Markov state model analysis
U2 - 10.1021/acschemneuro.7b00094
DO - 10.1021/acschemneuro.7b00094
M3 - Journal article
C2 - 28441487
VL - 8
SP - 1735
EP - 1746
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
SN - 1948-7193
IS - 8
ER -
ID: 183009780