Toward Understanding the Structural Basis of Partial Agonism at the Dopamine D₃ Receptor

Abstract

Both dopamine D3 receptor (D3R) partial agonists and antagonists have been implicated as potential medications for substance use disorders. In contrast to antagonists, partial agonists may cause fewer side effects since they maintain some dopaminergic tone and may be less disruptive to normal neuronal functions. Here, we report three sets of 4-phenylpiperazine stereoisomers that differ considerably in efficacy: the (R)-enantiomers are antagonists/weak partial agonists whereas the (S)-enantiomers are much more efficacious. To investigate the structural basis of partial agonism, we performed comparative microsecond-scale molecular dynamics simulations starting from the inactive state of D3R in complex with these enantiomers. Analysis of the simulation results reveals common structural rearrangements near the ligand binding site induced by the bound (S)-enantiomers, but not by the (R)-enantiomers, that are features of partially activated receptor conformations. These receptor models bound with partial agonists may be useful for structure-based design of compounds with tailored efficacy profiles.

Exploring Substrate Binding in the Extracellular Vestibule of MhsT by Atomistic Simulations and Markov Models

“…We developed the pairwise interaction analyzer for MhsT (PIA-MhsT), based on our previously developed PIA-GPCR 46 and PIA-DAT. 35 For the analysis of coarse-grained interaction network of MhsT at subsegment level, we used the following structural elements as previously defined: 17 NT (N terminus, residues 1–13), TM1i (the intracellular section (i) of TM1, 14–23), TM1m (the middle section (m) of TM1, 24–31), TM1e (the extracellular section (e) of TM1, 32–41), EL1 (42–44), TM2e (45–50), TM2m (51–60), TM2i (61–74), IL1 (the intracellular loop 1, 75–87), TM3i (88–103), TM3m (104–108), TM3e (109–124), EL2 (125–146), TM4e (147–155), TM4i (156–164), IL2 (165–171), TM5i (172–175), TM5m (176–181), TM5e (182–194), EL3 (195–217), TM6e (218–226), TM6m (227–238), TM6i (239–245), IL3 (246–252), TM7i (253–262), TM7m (263–269), TM7e (270–282), EL4a (283–288), EL4b (289–305), TM8e (306–319), TM8m (320–328), TM8i (329–338), IL4 (339–343), TM9i (344–353), TM9e (354–364), EL5 (365–379), TM10e (380–387), TM10m (388–392), TM10i (393–405), IL5 (406–426), and TM11 (427–448).…”

Distinct antagonist-bound inactive states underlie the divergence in the structures of the dopamine D2 and D3 receptors

“…The missing N terminus in the crystal structure was built de novo using Rosetta 33 , and then integrated with the rest of the D2R model using Modeller 34 . Using Modeller, we also extended two helical turns at the TM5 C terminus and threes residues at the TM6 N terminus of the structure and connected these two ends with a 9 Gly loop, similar to our experimentally validated treatment of D3R models 35 . The position of the Na + bound in the canonical Na + binding site near the negatively charged Asp 2.50 was acquired by superimposing the Na + bound structure of adenosine A2A receptor 36 to our D2R models.…”

“…The system charges were neutralized, and 150 mM NaCl was added. Each system was first minimized and then equilibrated with restraints on the ligand heavy atoms and protein backbone atoms, followed by production runs in an isothermal-isobaric (NPT) ensemble at 310 K and 1 atom with all atoms unrestrained, as described previously 19,35 .…”

“…While the majority of our D2R simulations in this study used the OPLS3 force field, to compare with the D3R simulations using CHARMM36 that have been continued from the previously reported shorter trajectories 19,35 , we carried out the D2R/eticlopride simulations using both the OPLS3 and CHARMM36 force fields (see Table S1). We did not observe significant differences and pooled their results together for the analysis.…”

“…To characterize the structural changes in the receptor upon ligand binding, we quantified differences of structural elements between the D2R/eticlopride and D2R/risperidone conditions (using last 600 ns from a representative trajectory for each condition), by applying the previously described pairwise interaction analyzer for GPCR (PIA-GPCR) 35 . The subsegments on the extracellular side of D2R were defined as following: TM1e (the extracellular subsegment (e) of TM1, residues 31-38), TM2e (residues 92-96), TM3e (residues 104-113), TM4e (residues 166-172), TM5e (residues 187-195), TM6e (residues 364-369), and TM7e (residues 376-382).…”