Conformation Guides Molecular Efficacy in Docking Screens of Activated β‑2 Adrenergic G Protein Coupled Receptor
A prospective, large library virtual screen against an activated β2-adrenergic receptor (β2AR) structure returned potent agonists to the exclusion of inverse-agonists, providing the first complement to the previous virtual screening campaigns against inverse-agonist-bound G protein coupled receptor...
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| Veröffentlicht in: | ACS chemical biology 2013-05, Vol.8 (5), p.1018-1026 |
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| creator | Weiss, Dahlia R Ahn, SeungKirl Sassano, Maria F Kleist, Andrew Zhu, Xiao Strachan, Ryan Roth, Bryan L Lefkowitz, Robert J Shoichet, Brian K |
| description | A prospective, large library virtual screen against an activated β2-adrenergic receptor (β2AR) structure returned potent agonists to the exclusion of inverse-agonists, providing the first complement to the previous virtual screening campaigns against inverse-agonist-bound G protein coupled receptor (GPCR) structures, which predicted only inverse-agonists. In addition, two hits recapitulated the signaling profile of the co-crystal ligand with respect to the G protein and arrestin mediated signaling. This functional fidelity has important implications in drug design, as the ability to predict ligands with predefined signaling properties is highly desirable. However, the agonist-bound state provides an uncertain template for modeling the activated conformation of other GPCRs, as a dopamine D2 receptor (DRD2) activated model templated on the activated β2AR structure returned few hits of only marginal potency. |
| doi_str_mv | 10.1021/cb400103f |
| format | Article |
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Biol</addtitle><description>A prospective, large library virtual screen against an activated β2-adrenergic receptor (β2AR) structure returned potent agonists to the exclusion of inverse-agonists, providing the first complement to the previous virtual screening campaigns against inverse-agonist-bound G protein coupled receptor (GPCR) structures, which predicted only inverse-agonists. In addition, two hits recapitulated the signaling profile of the co-crystal ligand with respect to the G protein and arrestin mediated signaling. This functional fidelity has important implications in drug design, as the ability to predict ligands with predefined signaling properties is highly desirable. However, the agonist-bound state provides an uncertain template for modeling the activated conformation of other GPCRs, as a dopamine D2 receptor (DRD2) activated model templated on the activated β2AR structure returned few hits of only marginal potency.</description><subject>Adrenergic beta-2 Receptor Agonists - chemistry</subject><subject>Adrenergic beta-2 Receptor Agonists - pharmacology</subject><subject>Benzoxazines</subject><subject>Binding Sites</subject><subject>Crystallography, X-Ray</subject><subject>Cyclic AMP - metabolism</subject><subject>Drug Evaluation, Preclinical - methods</subject><subject>Ethanolamines - chemistry</subject><subject>Ethanolamines - pharmacology</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Ligands</subject><subject>Models, Molecular</subject><subject>Molecular Docking Simulation</subject><subject>Morpholines - chemistry</subject><subject>Morpholines - pharmacology</subject><subject>Protein Conformation</subject><subject>Receptors, Adrenergic, beta-2 - chemistry</subject><subject>Receptors, Adrenergic, beta-2 - metabolism</subject><subject>Receptors, Dopamine D2 - chemistry</subject><subject>Receptors, G-Protein-Coupled - agonists</subject><subject>Receptors, G-Protein-Coupled - antagonists & inhibitors</subject><subject>Receptors, G-Protein-Coupled - chemistry</subject><subject>Small Molecule Libraries</subject><subject>Structural Homology, Protein</subject><issn>1554-8929</issn><issn>1554-8937</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>N~.</sourceid><sourceid>EIF</sourceid><recordid>eNptkUtuFDEQhi1ERB5kkQsgb5BgMUm5bfdjgzQakglSoiAga8tTrh4ceuzB7o6UHVfIVTgIh-AkdDTJCCRWLslffVWqn7EjAccCCnGCCwUgQLbP2J7QWk3qRlbPt3XR7LL9nG8AlCzr5gXbLaSqNZR6j-VZDG1MK9v7GPh88I4yv4wd4dDZxE_b1qPFO-4Dfx_xmw9L_hkTUcg8tnyKvb-1PTn-6-fvH_cFn7pEgdLSI5_zjyn2NDbO4rDuRuYTIa37mF6yndZ2mQ4f3wN2fXb6ZXY-ubiaf5hNLyZWge4nAp0lVCgVOlmJRaUFKYlOCyRQUFeqaIAsVAClA6KqgbpEKZyohWwrKQ_Yu413PSxW5JBCn2xn1smvbLoz0Xrz70_wX80y3hpZ6lprPQrePApS_D5Q7s3KZ6Sus4HikI2QWoISFZQj-naDYoo5J2q3YwSYh5DMNqSRffX3XlvyKZUReL0BLGZzE4cUxjP9R_QHBO6bFQ</recordid><startdate>20130517</startdate><enddate>20130517</enddate><creator>Weiss, Dahlia R</creator><creator>Ahn, SeungKirl</creator><creator>Sassano, Maria F</creator><creator>Kleist, Andrew</creator><creator>Zhu, Xiao</creator><creator>Strachan, Ryan</creator><creator>Roth, Bryan L</creator><creator>Lefkowitz, Robert J</creator><creator>Shoichet, Brian K</creator><general>American Chemical Society</general><scope>N~.</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20130517</creationdate><title>Conformation Guides Molecular Efficacy in Docking Screens of Activated β‑2 Adrenergic G Protein Coupled Receptor</title><author>Weiss, Dahlia R ; Ahn, SeungKirl ; Sassano, Maria F ; Kleist, Andrew ; Zhu, Xiao ; Strachan, Ryan ; Roth, Bryan L ; Lefkowitz, Robert J ; Shoichet, Brian K</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a405t-1cdaec4c34cd371b751e43cd51ce040874290ea07006d0ee79086c31d1813f733</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adrenergic beta-2 Receptor Agonists - chemistry</topic><topic>Adrenergic beta-2 Receptor Agonists - pharmacology</topic><topic>Benzoxazines</topic><topic>Binding Sites</topic><topic>Crystallography, X-Ray</topic><topic>Cyclic AMP - metabolism</topic><topic>Drug Evaluation, Preclinical - methods</topic><topic>Ethanolamines - chemistry</topic><topic>Ethanolamines - pharmacology</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Ligands</topic><topic>Models, Molecular</topic><topic>Molecular Docking Simulation</topic><topic>Morpholines - chemistry</topic><topic>Morpholines - pharmacology</topic><topic>Protein Conformation</topic><topic>Receptors, Adrenergic, beta-2 - chemistry</topic><topic>Receptors, Adrenergic, beta-2 - metabolism</topic><topic>Receptors, Dopamine D2 - chemistry</topic><topic>Receptors, G-Protein-Coupled - agonists</topic><topic>Receptors, G-Protein-Coupled - antagonists & inhibitors</topic><topic>Receptors, G-Protein-Coupled - chemistry</topic><topic>Small Molecule Libraries</topic><topic>Structural Homology, Protein</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Weiss, Dahlia R</creatorcontrib><creatorcontrib>Ahn, SeungKirl</creatorcontrib><creatorcontrib>Sassano, Maria F</creatorcontrib><creatorcontrib>Kleist, Andrew</creatorcontrib><creatorcontrib>Zhu, Xiao</creatorcontrib><creatorcontrib>Strachan, Ryan</creatorcontrib><creatorcontrib>Roth, Bryan L</creatorcontrib><creatorcontrib>Lefkowitz, Robert J</creatorcontrib><creatorcontrib>Shoichet, Brian K</creatorcontrib><collection>American Chemical Society (ACS) Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>ACS chemical biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Weiss, Dahlia R</au><au>Ahn, SeungKirl</au><au>Sassano, Maria F</au><au>Kleist, Andrew</au><au>Zhu, Xiao</au><au>Strachan, Ryan</au><au>Roth, Bryan L</au><au>Lefkowitz, Robert J</au><au>Shoichet, Brian K</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Conformation Guides Molecular Efficacy in Docking Screens of Activated β‑2 Adrenergic G Protein Coupled Receptor</atitle><jtitle>ACS chemical biology</jtitle><addtitle>ACS Chem. Biol</addtitle><date>2013-05-17</date><risdate>2013</risdate><volume>8</volume><issue>5</issue><spage>1018</spage><epage>1026</epage><pages>1018-1026</pages><issn>1554-8929</issn><eissn>1554-8937</eissn><abstract>A prospective, large library virtual screen against an activated β2-adrenergic receptor (β2AR) structure returned potent agonists to the exclusion of inverse-agonists, providing the first complement to the previous virtual screening campaigns against inverse-agonist-bound G protein coupled receptor (GPCR) structures, which predicted only inverse-agonists. In addition, two hits recapitulated the signaling profile of the co-crystal ligand with respect to the G protein and arrestin mediated signaling. This functional fidelity has important implications in drug design, as the ability to predict ligands with predefined signaling properties is highly desirable. 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| source | ACS Publications; MEDLINE |
| subjects | Adrenergic beta-2 Receptor Agonists - chemistry Adrenergic beta-2 Receptor Agonists - pharmacology Benzoxazines Binding Sites Crystallography, X-Ray Cyclic AMP - metabolism Drug Evaluation, Preclinical - methods Ethanolamines - chemistry Ethanolamines - pharmacology HEK293 Cells Humans Ligands Models, Molecular Molecular Docking Simulation Morpholines - chemistry Morpholines - pharmacology Protein Conformation Receptors, Adrenergic, beta-2 - chemistry Receptors, Adrenergic, beta-2 - metabolism Receptors, Dopamine D2 - chemistry Receptors, G-Protein-Coupled - agonists Receptors, G-Protein-Coupled - antagonists & inhibitors Receptors, G-Protein-Coupled - chemistry Small Molecule Libraries Structural Homology, Protein |
| title | Conformation Guides Molecular Efficacy in Docking Screens of Activated β‑2 Adrenergic G Protein Coupled Receptor |
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