Modelling of dopamine D<sub>3</sub> receptor in complex with eticlopride: development and validation of methodology — ASN Events
  1. Schedule
  2. Session Twelve - Poster Session D including Happy Hour & Trade Display
  3. Modelling of dopamine D3 receptor in complex with eticlopride: development and validation of methodology

Modelling of dopamine D3 receptor in complex with eticlopride: development and validation of methodology (#412)

Kaniz F Urmi 1 , Angela M Finch 1 , Renate Griffith 1
  1. UNSW Australia, Sydney, NSW, Australia

Improved modelling of G protein-coupled receptor- (GPCR-) ligand complexes is an important first step for structure-based drug design. As only a few GPCR crystal structures are available to date, accurate modelling of GPCR-ligand complexes can assist in the design of more selective drugs.

We are currently developing a methodology to build homology models, dock ligands, and refine the docked poses.

To validate our methodology we have built homology models of the dopamine D3 receptor (D3-R) as a crystal structure of this receptor in complex with eticlopride has been solved (PDB ID: 3PBL) [1]. Several crystal structures were selected as templates based on sequence similarity according to phylogenetic relationships [2] and on ligand similarity [3]. Homology models were prepared using Modeller [4]. Eticlopride was docked into the highest-scoring models, according to the PDF total energy score, using Gold (http://www.ccdc.cam.ac.uk/products/gold_suite). In each case, a second high-scoring model with a different binding pocket was also chosen for docking by clustering using TRAPP [5]. The ligand poses were evaluated by Goldscores and interactions formed and selected poses were refined by minimisations and short molecular dynamics simulations under various conditions.  Docked poses and refined poses were then compared to the D3-R-eticlopride crystal structure by superimposition.

The findings of this analysis will provide us with guidelines for more accurate prediction of GPCR-drug complexes.      

  1. Chien EY, Liu W, Zhao Q, Katritch V, Han GW, Hanson MA, et al. (2010). Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Science 330(6007): 1091-1095.
  2. Stevens RC, Cherezov V, Katritch V, Abagyan R, Kuhn P, Rosen H, et al. (2013). The GPCR Network: a large-scale collaboration to determine human GPCR structure and function. Nature reviews. Drug discovery 12(1): 25-34.
  3. Lin H, Sassano MF, Roth BL, Shoichet BK (2013). A pharmacological organization of G protein-coupled receptors. Nature methods 10(2): 140-146.
  4. Sali A, Blundell TL (1993). Comparative protein modelling by satisfaction of spatial restraints. Journal of Molecular Biology 234(3): 779-815.
  5. Kokh DB, Richter S, Henrich S, Czodrowski P, Rippmann F, Wade RC (2013). TRAPP: a tool for analysis of transient binding pockets in proteins. Journal of chemical information and modeling 53(5): 1235-1252.