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About the Authors:
Peter Kolb
* E-mail: [email protected] (PK); [email protected] (KAJ)
Current address: Department of Pharmaceutical Chemistry, Philipps-University Marburg, Marburg, Germany
Affiliation: Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, United States of America
Khai Phan
Affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
Zhan-Guo Gao
Affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
Adam C. Marko
Current address: Asuragen Inc., Austin, Texas, United States of America
Affiliations Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, United States of America, Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America
Andrej Sali
Affiliations Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, United States of America, Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America
Kenneth A. Jacobson
* E-mail: [email protected] (PK); [email protected] (KAJ)
Affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
Introduction
G protein-coupled receptors (GPCRs) are one of the pharmaceutically most important protein families, and the targets of around one third of present day drugs [1]. They mediate the transmission of signals from the exterior to the interior of a cell by binding signaling agents and, via conformational changes, eliciting intracellular responses. GPCRs consist of seven membrane-crossing helices. The binding pockets of the native small molecule ligands, i.e. orthosteric binding sites, are situated in the middle of the helical bundle in the Class A GPCR structures that have been determined so far [2]. Despite the recent advances in GPCR X-ray structure determination [3] and the substantial numbers of novel ligands identified for some GPCRs [4], [5], there are still many (potential) GPCR targets for which no structure or ligands are known. In order to apply protein structure-based methods of ligand identification, in particular docking, to receptors that lack an experimentally determined structure, homology modeling is a promising avenue....