Factors Governing Selectivity of Dopamine Receptor Binding Compounds for D2R and D3R Subtypes

Abstract

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.

Recent advances in dopamine D2 receptor ligands in the treatment of neuropsychiatric disorders

“…On the other hand, EL2 was observed to be more exposed to the binding pocket in D 3 compared to D 2 receptors. Molecular mechanics Poisson–Boltzmann surface area calculations indicated that Trp EL1 contributes more to the binding energies of 4a–b in D 2 compared to D 3 receptors, while Lys EL2 in EL2 exhibited an undesirable impact on binding energies in D 2 Rs 491 …”

“…1‐[2‐(2‐Fluoroethoxy)phenyl]piperazine derivatives ( 4, 4a–b , Figure 7) were chosen to understand why adding different moieties like 4‐(thiophen‐3‐yl)benzamide (in 4a ) versus 3,4‐dihydro‐2(1 H )‐quinolinone (in 4b ) to the short ligand 4 modulates their selectivity for D 3 or D 2 receptors 491 . In cumulative simulations, there were various hydration patterns in the second binding site in D 2 or D 3 receptors.…”

“…For D 2 R, the orthosteric binding site or ligand‐binding site was covered by the C ‐terminal segment of the extracellular loop 2, which is stabilized by a disulfide bond between Cys107 3.25 on transmembrane helix 3 and Cys182 42.50 on extracellular loop 2 70,524 . Endogenous ligand (DA) and phenylpiperazines bind this binding site 471,489,491,508,525–527 . The binding of these ligands is stabilized by a salt bridge between Asp114 3.32 in transmembrane helix 3 and the protonated nitrogen on the piperazine ring or aliphatic amine in DA molecule 70,471,525,526,528 .…”

“…490 1-[2-(2-Fluoroethoxy)phenyl]piperazine derivatives (4, 4a-b, while Lys EL2 in EL2 exhibited an undesirable impact on binding energies in D 2 Rs. 491 Between the years 2010-2022, a large number of studies were reported describing the identification of fragments responsible for selectivity for D 3 Rs. 467,[492][493][494][495][496][497][498][499][500] However, these receptors do not represent primary focus of this review and will therefore not be commented.…”

“…70,524 Endogenous ligand (DA) and phenylpiperazines bind this binding site. 471,489,491,508,[525][526][527] The binding of these ligands is stabilized by a salt bridge between Asp114 3.32 in transmembrane helix 3 and the protonated nitrogen on the piperazine ring or aliphatic amine in DA molecule. 70,471,525,526,528 On the other hand, the allosteric binding site (also referred as a secondary binding site) is the area where moiety (in most cases, aromatic/heteroaromatic lipohilic fragment), connected via the optimal central linker with arylpiperazines, binds.…”