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Pharmaceuticals 2011, 4(9), 1196-1215; doi:10.3390/ph4091196

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 / Revised: 23 August 2011 / Accepted: 29 August 2011 / Published: 1 September 2011
(This article belongs to the Special Issue Advances in Drug Design)
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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. View Full-Text
Keywords: comparative modeling; ligand binding mode prediction; G protein-coupled receptor (GPCR); GPCR Dock 2010 comparative modeling; ligand binding mode prediction; G protein-coupled receptor (GPCR); GPCR Dock 2010

This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

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.

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