TY - JOUR
T1 - Factors Governing Selectivity of Dopamine Receptor Binding Compounds for D2R and D3R Subtypes
AU - Hayatshahi, Hamed S.
AU - Luedtke, Robert R.
AU - Taylor, Michelle
AU - Chen, Peng Jen
AU - Blass, Benjamin E.
AU - Liu, Jin
N1 - Funding Information:
The authors would like to thank Robert H. Mach at the University of Pennsylvania School of Medicine for his assistance in this project. We also appreciate the resources provided by the High Performance Computing (HPC) center at the University of North Texas (UNT). The research reported in this publication was partly supported by the National Institute on Drug Abuse (NIDA)/National Institutes of Health (NIH) under award number 2R01DA023957. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2021 American Chemical Society.
PY - 2021/6/28
Y1 - 2021/6/28
N2 - Targeting the D3 dopamine receptor (D3R) is a promising pharmacotherapeutic strategy for the treatment of many disorders. The structure of the D3R is similar to the D2 dopamine receptor (D2R), especially in the transmembrane spanning regions that form the orthosteric binding site, making it difficult to identify D3R selective pharmacotherapeutic agents. Here, we examine the molecular basis for the high affinity D3R binding and D3R vs D2R binding selectivity of substituted phenylpiperazine thiopheneamides. We show that removing the thiophenearylamide portion of the ligand consistently decreases the affinity of these ligands at D3R, while not affecting their affinity at the D2R. Our long (>10 μs) molecular dynamics simulations demonstrated that both dopamine receptor subtypes adopt two major conformations that we refer to as closed or open conformations, with D3R sampling the open conformation more frequently than D2R. The binding of ligands with conjoined orthosteric-allosteric binding moieties causes the closed conformation to populate more often in the trajectories. Also, significant differences were observed in the extracellular loops (ECL) of these two receptor subtypes leading to the identification of several residues that contribute differently to the ligand binding for the two receptors that could potentially contribute to ligand binding selectivity. Our observations also suggest that the displacement of ordered water in the binding pocket of D3R contributes to the affinity of the compounds containing an allosteric binding motif. These studies provide a better understanding of how a bitopic mode of engagement can determine ligands that bind selectively to D2 and D3 dopamine receptor subtypes.
AB - Targeting the D3 dopamine receptor (D3R) is a promising pharmacotherapeutic strategy for the treatment of many disorders. The structure of the D3R is similar to the D2 dopamine receptor (D2R), especially in the transmembrane spanning regions that form the orthosteric binding site, making it difficult to identify D3R selective pharmacotherapeutic agents. Here, we examine the molecular basis for the high affinity D3R binding and D3R vs D2R binding selectivity of substituted phenylpiperazine thiopheneamides. We show that removing the thiophenearylamide portion of the ligand consistently decreases the affinity of these ligands at D3R, while not affecting their affinity at the D2R. Our long (>10 μs) molecular dynamics simulations demonstrated that both dopamine receptor subtypes adopt two major conformations that we refer to as closed or open conformations, with D3R sampling the open conformation more frequently than D2R. The binding of ligands with conjoined orthosteric-allosteric binding moieties causes the closed conformation to populate more often in the trajectories. Also, significant differences were observed in the extracellular loops (ECL) of these two receptor subtypes leading to the identification of several residues that contribute differently to the ligand binding for the two receptors that could potentially contribute to ligand binding selectivity. Our observations also suggest that the displacement of ordered water in the binding pocket of D3R contributes to the affinity of the compounds containing an allosteric binding motif. These studies provide a better understanding of how a bitopic mode of engagement can determine ligands that bind selectively to D2 and D3 dopamine receptor subtypes.
UR - http://www.scopus.com/inward/record.url?scp=85106476583&partnerID=8YFLogxK
U2 - 10.1021/acs.jcim.1c00036
DO - 10.1021/acs.jcim.1c00036
M3 - Article
C2 - 33988991
AN - SCOPUS:85106476583
SN - 1549-9596
VL - 61
SP - 2829
EP - 2843
JO - Journal of Chemical Information and Modeling
JF - Journal of Chemical Information and Modeling
IS - 6
ER -