Progress in the structural prediction of G protein‐coupled receptors: D₃ receptor in complex with eticlopride

Abstract

Predicting the three-dimensional structure of ligand-receptor complexes involving G protein-coupled receptors (GPCRs) is still a challenging task in rational drug design. To evaluate the reliability of the GPCR structural prediction, only a couple of community-wide assessments have been carried out. Our participation in the last edition, DOCK2010, involved the blind prediction of the dopaminergic D(3) receptor in complex with the D(2)/D(3) selective antagonist eticlopride for which the crystal structure has been recently released. Here, we describe a methodology that succeeded to produce a correctly predicted eticlopride-D(3) receptor complex out of three submitted models. Ranking the obtained models in the correct order is the main challenge due to subtle structural differences in the complex that are not sufficiently captured by conventional scoring functions. Importantly, our work reveals that a correct ranking is obtained by including a more sophisticated description of conformational ligand energy on binding. All in all, this case study highlights the current progress in modeling GPCR complexes and underlines that in silico modeling can be a valuable complement in GPCR drug discovery.

Towards predictive docking at aminergic G-protein coupled receptors

“…It has been shown, however, that standard MD may improve docking poses of various targets [30] including GPCRs [33,34]. Similar to our study, Orbiol-Pardo et al [32] showed that MD substantially affects the conformation of ECL2 and improves docking of ecticlopride to the D 3 receptor. In most cases, our study demonstrated that simulation of hundreds of nanoseconds of conventional MD eliminates differences between the top pose and crystal structure in interacting with the receptor.…”

“…Analysis of ligand-receptor interactions shows that, in agreement with previous findings [32,48], modeling of ligand interactions with ECL2 was most problematic (Fig. 2, Table 6 and Supplementary Information Text File S1).…”

“…A less explored way to improve docking results is via a combination of docking and molecular dynamics (MD). Improvement of docked ligand-receptor complexes by MD has been demonstrated for various targets [31] including GPCR [32][33][34]. In our study of 11 structures of aminergic GPCRs, we show convergence in 9 out of 11 MD trajectories of top poses and crystal structures upon MD simulation and identification of key ligand-receptor interactions from MD trajectories in all cases.…”

Detection of New Biased Agonists for the Serotonin 5-HT2A Receptor: Modeling and Experimental Validation

“…Both compounds, the natural ligand serotonin (used as a control for balanced agonism) and 2C-N, were docked into a fully activated model of the serotonin 5-HT 2A receptor. Notably, the modeling approach used to obtain these ligand-receptor complexes, which is detailed in the Materials and Methods section, has previously proven to be highly effective in predicting highresolution ligand-receptor complexes for related targets (Obiol-Pardo et al, 2011). The resulting complexes were embedded into a hydrated lipid bilayer, ionized to a physiologic concentration and subjected to extensive molecular dynamic simulations.…”

Open challenges in structure-based virtual screening: Receptor modeling, target flexibility consideration and active site water molecules description

“…Then, models for dopamine D(2), D(3), and D(4), serotonin 5-HT(1B), 5-HT(2A), 5-HT(2B), and 5-HT(2C), histamine H(1), and muscarinic M(1) receptors were generated using as template the structure of the β₂-adrenergic receptor [70] and assessed in high-throughput docking campaigns [71]. This strategy was also applied in the blind prediction of the D(3) receptor structure complexed with the D(2)/D(3) selective antagonist eticlopride (GPCR DOCK 2010 challenge [44]), where a successful prediction was achieved in one out of three submitted models [72]. A detailed description of the modeling of 5-hydroxytryptamine receptors 1B and 2B in GPCR DOCK 2013 can be found elsewhere [53].…”