Document Detail

In silico screening for agonists and blockers of the β(2) adrenergic receptor: implications of inactive and activated state structures.
MedLine Citation:
PMID:  22170280     Owner:  NLM     Status:  MEDLINE    
Ten crystal structures of the β(2) adrenergic receptor have been published, reflecting different signaling states. Here, through controlled-docking experiments, we examined the implications of using inactive or activated structures on the in silico screening for agonists and blockers of the receptor. Specifically, we targeted the crystal structures solved in complex with carazolol (2RH1), the neutral antagonist alprenalol, the irreversible agonist FAUC50 (3PDS), and the full agonist BI-167017 (3P0G). Our results indicate that activated structures favor agonists over blockers, whereas inactive structures favor blockers over agonists. This tendency is more marked for activated than for inactive structures. Additionally, agonists tend to receive more favorable docking scores when docked at activated rather than inactive structures, while blockers do the opposite. Hence, the difference between the docking scores attained with an activated and an inactive structure is an excellent means for the classification of ligands into agonists and blockers as we determined through receiver operating characteristic curves and linear discriminant analysis. With respect to virtual screening, all structures prioritized well agonists and blockers over nonbinders. However, inactive structures worked better for blockers and activated structures worked better for agonists, respectively. Notably, the combination of individual docking experiments through receptor ensemble docking resulted in an excellent performance in the retrieval of both agonists and blockers. Finally, we demonstrated that the induced-fit docking of agonists is a viable way of modifying an inactive crystal structure and bias it toward the in silico recognition of agonists rather than blockers.
Stefano Costanzi; Santiago Vilar
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural     Date:  2011-12-14
Journal Detail:
Title:  Journal of computational chemistry     Volume:  33     ISSN:  1096-987X     ISO Abbreviation:  J Comput Chem     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-01-24     Completed Date:  2012-05-07     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  9878362     Medline TA:  J Comput Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  561-72     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Wiley Periodicals, Inc.
Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, Maryland 20892, USA.
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MeSH Terms
Adrenergic beta-Agonists / chemistry*
Adrenergic beta-Antagonists / chemistry*
Crystallography, X-Ray
Models, Molecular
Molecular Structure
Receptors, Adrenergic, beta-2 / drug effects*
Grant Support
Reg. No./Substance:
0/Adrenergic beta-Agonists; 0/Adrenergic beta-Antagonists; 0/Receptors, Adrenergic, beta-2

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