In Silico Veritas: The Pitfalls and Challenges of Predicting GPCR-Ligand Interactions

Pharmaceuticals

Luc Roumen¹  Marijn P.A. Sanders³  Bas Vroling³  Iwan J.P. de Esch¹  Jacob de Vlieg³  Rob Leurs¹  Jan P.G. Klomp²  Sander B. Nabuurs³ 

[1] Department of Medicinal Chemistry, VU University Amsterdam, De Boelelaan 1081, Amsterdam 1081 HV, The Netherlands; E-Mails:;Department of Molecular Design and Informatics, MRL, MSD, Oss 2031 BN, The Netherlands; E-Mail:;CMBI, NCMLS, Radboud University Nijmegen Medical Centre, Geert Grooteplein Zuid 26-28, Nijmegen 6525 GA, The Netherlands; E-Mails:

关键词: comparative modeling;    ligand binding mode prediction;    G protein-coupled receptor (GPCR);    GPCR Dock 2010;   

DOI  :  10.3390/ph4091196

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2011 by the authors; licensee MDPI, Basel, Switzerland.