Community-wide assessment of GPCR structure modelling and ligand docking: GPCR Dock 2008

Key Points To evaluate current progress in GPCR structure prediction and ligand docking, a community-wide prediction assessment — GPCR Dock 2008 — in coordination with the publication of the human adenosine A 2A receptor structure in October 2008 and public release of the 3-dimensional coordinates. Twenty-nine groups submitted 206 structural models before the release of the experimental structure. The structures were evaluated for the accuracy of the ligand binding mode and the overall receptor model compared with the crystal structure. The majority of the submitted models predicted the overall topology, but did not predict the ligand position and the binding interactions very accurately. The best model overall (submitted by S. Costanzi) has a ligand RMSD of 2.8 Å RMSD and 34 of 75 correct contacts. Accurate modelling of the structurally divergent regions (such as the extracellular loops), of disulphide bond formation affecting helix residue registry and of the helical shifts in the TM region seem to be crucial for accurately predicting the key ligand interactions in GPCRs, and this area is perhaps the most in need of technological development. The recent determination of several crystal structures of G protein-coupled receptors (GPCRs) is providing new opportunities for structure-based drug design. This article analyses the state of the art in the prediction of GPCR structure and the docking of potential ligands on the basis of a community-wide, blind prediction assessment — GPCR Dock 2008 — that was carried out in coordination with the publication of the human adenosine A 2A receptor structure in 2008 and public release of the three-dimensional coordinates. Recent breakthroughs in the determination of the crystal structures of G protein-coupled receptors (GPCRs) have provided new opportunities for structure-based drug design strategies targeting this protein family. With the aim of evaluating the current status of GPCR structure prediction and ligand docking, a community-wide, blind prediction assessment — GPCR Dock 2008 — was conducted in coordination with the publication of the crystal structure of the human adenosine A 2A receptor bound to the ligand ZM241385. Twenty-nine groups submitted 206 structural models before the release of the experimental structure, which were evaluated for the accuracy of the ligand binding mode and the overall receptor model compared with the crystal structure. This analysis highlights important aspects for success and fut