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In Silico Veritas: The Pitfalls and Challenges of Predicting GPCR-Ligand Interactions
Department of Medicinal Chemistry, VU University Amsterdam, De Boelelaan 1081, Amsterdam 1081 HV, The Netherlands
CMBI, NCMLS, Radboud University Nijmegen Medical Centre, Geert Grooteplein Zuid 26-28, Nijmegen 6525 GA, The Netherlands
Department of Molecular Design and Informatics, MRL, MSD, Oss 2031 BN, The Netherlands
* Author to whom correspondence should be addressed.
Received: 5 August 2011; in revised form: 23 August 2011 / Accepted: 29 August 2011 / Published: 1 September 2011
Abstract: Recently the first community-wide assessments of the prediction of the structures of complexes between proteins and small molecule ligands have been reported in the so-called GPCR Dock 2008 and 2010 assessments. In the current review we discuss the different steps along the protein-ligand modeling workflow by critically analyzing the modeling strategies we used to predict the structures of protein-ligand complexes we submitted to the recent GPCR Dock 2010 challenge. These representative test cases, focusing on the pharmaceutically relevant G Protein-Coupled Receptors, are used to demonstrate the strengths and challenges of the different modeling methods. Our analysis indicates that the proper performance of the sequence alignment, introduction of structural adjustments guided by experimental data, and the usage of experimental data to identify protein-ligand interactions are critical steps in the protein-ligand modeling protocol.
Keywords: comparative modeling; ligand binding mode prediction; G protein-coupled receptor (GPCR); GPCR Dock 2010
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Roumen, L.; Sanders, M.P.; Vroling, B.; De Esch, I.J.; De Vlieg, J.; Leurs, R.; Klomp, J.P.; Nabuurs, S.B.; De Graaf, C. In Silico Veritas: The Pitfalls and Challenges of Predicting GPCR-Ligand Interactions. Pharmaceuticals 2011, 4, 1196-1215.
Roumen L, Sanders MP, Vroling B, De Esch IJ, De Vlieg J, Leurs R, Klomp JP, Nabuurs SB, De Graaf C. In Silico Veritas: The Pitfalls and Challenges of Predicting GPCR-Ligand Interactions. Pharmaceuticals. 2011; 4(9):1196-1215.
Roumen, Luc; Sanders, Marijn P.A.; Vroling, Bas; De Esch, Iwan J.P.; De Vlieg, Jacob; Leurs, Rob; Klomp, Jan P.G.; Nabuurs, Sander B.; De Graaf, Chris. 2011. "In Silico Veritas: The Pitfalls and Challenges of Predicting GPCR-Ligand Interactions." Pharmaceuticals 4, no. 9: 1196-1215.