Status of GPCR modeling and docking as reflected by community-wide GPCR Dock 2010 assessment

By Irina Kufareva, Manuel Rueda, Vsevolod Katritch, Raymond C. Stevens, Ruben Abagyan. 2011

283 citations recorded by the source corpus.

Summary The community-wide GPCR Dock assessment is conducted to evaluate the status of molecular modeling and ligand docking for human G-protein coupled receptors. The present round of the assessment was based on the recent structures of dopamine D3 and CXCR4 chemokine receptors bound to small molecule antagonists and CXCR4 with a synthetic cyclopeptide. Thirty five groups submitted their receptor-ligand complex structure predictions prior to the release of the crystallographic coordinates. With closely related experimentally determined homology templates, as for dopamine D3 receptor, and with incorporation of biochemical and QSAR data, modern computational techniques predicted complex details with accuracy approaching experimental. In contrast, CXCR4 complexes that had less characterized interactions and only distant homology to the known GPCR structures still remained very challenging. The assessment results provide guidance for modeling and crystallographic communities in method development and target selection for further expansion of the structural coverage of the GPCR universe.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Radiology, Nuclear Medicine and Imaging

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Citations in the corpus

Improving homology modeling from low-sequence identity templates in Rosetta: A case study in GPCRs (2020, methodology): “In the GPCR Dock experiment [21], Rosetta performed best in the structure prediction of the Smoothened receptor ligand binding pose [22].”
Docking and scoring with ICM: the benchmarking results and strategies for improvement (2012, methodology): “Both symmetry corrected RMSD and contact measures were also used in the GPCRdock evaluation [44] and are publically accessible at the laboratory web server Simicon, http://aba gyan.”
Protein-ligand docking in the new millennium--a retrospective of 10 years in the field. (2013, background): “Other interesting alternative is the evaluation of the performance of specific docking tools in well-defined structure-prediction challenges, such as the GPCR Dock assessment [203-205].”
Structure-based drug screening for G-protein-coupled receptors. (2012, background): “The community had been challenged to predict D3 dopamine receptor/eticlopride complex, as well as complexes involving the CXCR4 receptor, before their x-ray structure were released [33, 34].”
Latest developments in molecular docking: 2010–2011 in review (2013, background): “[151] It involved modeling structures of the dopamine D 3 and CXCR4 chemokine receptors, bound to small-molecule antagonists, and CXCR4 complexed with a peptide.”
GPCRdb: the G protein‐coupled receptor database – an introduction (2016, background): “As indicated by the three community-wide ‘GPCR Dock’ assessments, the increasing number of structural templates has led to higher precision in homology modelling (Michino et al., 2009; Kufareva et al., 2011; Kufareva et al., 2014).”
Microscale Thermophoresis Quantifies Biomolecular Interactions under Previously Challenging Conditions (2012, unknown): “Clearly, a combination of structural knowledge, ligand docking [38,39] and fast and reliable technologies for measurement of ligand binding affinities are necessary and indispensable tools for next generation drug discovery efforts.”
Assessment and Challenges of Ligand Docking into Comparative Models of G-Protein Coupled Receptors (2013, background): “Primary reasons include a lack of adequate template structures, the existence of multi-conformational states which require intense conformational sampling of not only the protein side chain but also backbone conformational space, in combination with the large variety of ligands that interact with GP”
Protein Modelling: What Happened to the “Protein Structure Gap”? (2013, unknown): “Similar to protein structure prediction, community efforts for blind and independent validation of prediction techniques are crucial to assess the expected accuracy and reliability of modeled protein-ligand interactions (Damm-Ganamet et al., 2013; Kufareva et al., 2011; SAMPL, 2010).”
GOMoDo: A GPCRs Online Modeling and Docking Webserver (2013, background): “Nonetheless, homology modeling has succeeded in predicting ligand-target interactions information for several different GPCRs [3–6].”