G-Protein/β-Arrestin-Linked Fluctuating Network of G-Protein-Coupled Receptors for Predicting Drug Efficacy and Bias Using Short-Term Molecular Dynamics Simulation
Publication Date
May 17, 2016
Journal
PLOS ONE
Authors
Osamu Ichikawa, Kazushi Fujimoto, Atsushi Yamada, Susumu Okazaki, et al
Volume
11
Issue
5
Pages
e0155816
DOI
https://dx.plos.org/10.1371/journal.pone.0155816
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0155816
Scopus
84969528666
Mendeley
http://www.mendeley.com/research/gprotein%CE%B2arrestinlinked-fluctuating-network-gproteincoupled-receptors-predicting-drug-efficacy-bias
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Mendeley | Further Information

{"title"=>"G-Protein/β-arrestin-linked fluctuating network of G-protein-coupled receptors for predicting drug efficacy and bias using short-term molecular dynamics simulation", "type"=>"journal", "authors"=>[{"first_name"=>"Osamu", "last_name"=>"Ichikawa", "scopus_author_id"=>"56348322300"}, {"first_name"=>"Kazushi", "last_name"=>"Fujimoto", "scopus_author_id"=>"55628535051"}, {"first_name"=>"Atsushi", "last_name"=>"Yamada", "scopus_author_id"=>"55727927200"}, {"first_name"=>"Susumu", "last_name"=>"Okazaki", "scopus_author_id"=>"7202222671"}, {"first_name"=>"Kazuto", "last_name"=>"Yamazaki", "scopus_author_id"=>"35352712200"}], "year"=>2016, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84969528666", "doi"=>"10.1371/journal.pone.0155816", "pui"=>"610398122", "pmid"=>"27187591", "scopus"=>"2-s2.0-84969528666", "issn"=>"19326203"}, "id"=>"3b196298-fa63-371b-8b87-067b4338802e", "abstract"=>"The efficacy and bias of signal transduction induced by a drug at a target protein are closely associated with the benefits and side effects of the drug. In particular, partial agonist activity and G-protein/β-arrestin-biased agonist activity for the G-protein-coupled receptor (GPCR) family, the family with the most target proteins of launched drugs, are key issues in drug discovery. However, designing GPCR drugs with appropriate efficacy and bias is challenging because the dynamic mechanism of signal transduction induced by ligand-receptor interactions is complicated. Here, we identified the G-protein/β-arrestin-linked fluctuating network, which initiates large-scale conformational changes, using sub-microsecond molecular dynamics (MD) simulations of the β2-adrenergic receptor (β2AR) with a diverse collection of ligands and correlation analysis of their G protein/β-arrestin efficacy. The G-protein-linked fluctuating network extends from the ligand-binding site to the G-protein-binding site through the connector region, and the β-arrestin-linked fluctuating network consists of the NPxxY motif and adjacent regions. We confirmed that the averaged values of fluctuation in the fluctuating network detected are good quantitative indexes for explaining G protein/β-arrestin efficacy. These results indicate that short-term MD simulation is a practical method to predict the efficacy and bias of any compound for GPCRs.", "link"=>"http://www.mendeley.com/research/gprotein%CE%B2arrestinlinked-fluctuating-network-gproteincoupled-receptors-predicting-drug-efficacy-bias", "reader_count"=>22, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>2, "Researcher"=>7, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>8, "Student > Postgraduate"=>1, "Student > Bachelor"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>2, "Researcher"=>7, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>8, "Student > Postgraduate"=>1, "Student > Bachelor"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>6, "Agricultural and Biological Sciences"=>8, "Pharmacology, Toxicology and Pharmaceutical Science"=>5, "Chemistry"=>2, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Chemistry"=>{"Chemistry"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>8}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>6}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>5}}, "reader_count_by_country"=>{"Switzerland"=>1}, "group_count"=>0}

Scopus | Further Information

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