Scopus Publication Detail
The publication detail shows the title, authors (with indicators showing other profiled authors), information on the publishing organization, abstract and a link to the article in Scopus. This abstract is what is used to create the fingerprint of the publication.
Do crystal structures obviate the need for theoretical models of GPCRs for structure-based virtual screening?
Hao Tang; Xiang Simon Wang; Jui-Hua Hsieh; Alexander Tropsha(Profiled Author: Hao Tang)
Proteins: Structure, Function and Bioinformatics. 2012;80(6):1503-1521.Abstract
Recent highly expected structural characterizations of agonist-bound and antagonist-bound beta-2 adrenoreceptor (β2AR) by X-ray crystallography have been widely regarded as critical advances to enable more effective structure-based discovery of GPCRs ligands. It appears that this very important development may have undermined many previous efforts to develop 3D theoretical models of GPCRs. To address this question directly, we have compared several historical β2AR models versus the inactive state and nanobody-stabilized active state of β2AR crystal structures in terms of their structural similarity and effectiveness of use in virtual screening for β2AR specific agonists and antagonists. Theoretical models, incluing both homology and de novo types, were collected from five different groups who have published extensively in the field of GPCRs modeling. All models were built before X-ray structures became available. In general, β2AR theoretical models differ significantly from the crystal structure in terms of TMH definition and the global packing. Nevertheless, surprisingly, several models afforded hit rates resulting from virtual screening of large chemical library enriched by known β2AR ligands that exceeded those using X-ray structures. The hit rates were particularly higher for agonists. Furthemore, the screening performance of models is associated with local structural quality, such as the RMSDs for binding pocket residues and the ability to capture accurately, most if not all critical protein/ligand interactions. These results suggest that carefully built models of GPCRs could capture critical chemical and structural features of the binding pocket, and thus may be even more useful for practical structure-based drug discovery than X-ray structures. © 2012 Wiley Periodicals, Inc.
This section shows information related to the publication - computed using the fingerprint of the publication - including related publications, related experts with fingerprints representing significant amounts of overlap between their fingerprint and this publication. The red dots indicate whether those experts or terms appear within the publication, thereby showing potential and actual connections.
Daniel M. Rosenbaum; Cheng Zhang; Joseph A. Lyons; Ralph Holl; David Aragao; Daniel H. Arlow; Sã̧ren G.F. Rasmussen; Hee-Jung Choi; Brian T. Devree; Roger K. Sunahara; et al.Nature. 2011;469(7329):236-242.
Søren G. F. Rasmussen; Hee-Jung Choi; Juan Jose Fung; Els Pardon; Paola Casarosa; Pil Seok Chae; Brian T. Devree; Daniel M. Rosenbaum; Foon Sun Thian; Tong Sun Kobilka; et al.Nature. 2011;469(7329):175-181.
Peter Kolb; Daniel M. Rosenbaum; John J. Irwin; Juan José Fung; Brian K. Kobilka; Brian K. ShoichetProceedings of the National Academy of Sciences of the United States of America. 2009;106(16):6843-6848.
Appears in this Document