Publication Date:
2006-04-22
Description:
G protein betagamma subunits have potential as a target for therapeutic treatment of a number of diseases. We performed virtual docking of a small-molecule library to a site on Gbetagamma subunits that mediates protein interactions. We hypothesized that differential targeting of this surface could allow for selective modulation of Gbetagamma subunit functions. Several compounds bound to Gbetagamma subunits with affinities from 0.1 to 60 muM and selectively modulated functional Gbetagamma-protein-protein interactions in vitro, chemotactic peptide signaling pathways in HL-60 leukocytes, and opioid receptor-dependent analgesia in vivo. These data demonstrate an approach for modulation of G protein-coupled receptor signaling that may represent an important therapeutic strategy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bonacci, Tabetha M -- Mathews, Jennifer L -- Yuan, Chujun -- Lehmann, David M -- Malik, Sundeep -- Wu, Dianqing -- Font, Jose L -- Bidlack, Jean M -- Smrcka, Alan V -- GM60286/GM/NIGMS NIH HHS/ -- HL-T3207949/HL/NHLBI NIH HHS/ -- HL080706/HL/NHLBI NIH HHS/ -- K05-DA00360/DA/NIDA NIH HHS/ -- R01 CA132317/CA/NCI NIH HHS/ -- R01 GM054597/GM/NIGMS NIH HHS/ -- R01 GM054597-09/GM/NIGMS NIH HHS/ -- R01 HL080706/HL/NHLBI NIH HHS/ -- R01 HL080706-10/HL/NHLBI NIH HHS/ -- R01 HL080706-11/HL/NHLBI NIH HHS/ -- T32DA07232/DA/NIDA NIH HHS/ -- New York, N.Y. -- Science. 2006 Apr 21;312(5772):443-6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/16627746" target="_blank"〉PubMed〈/a〉
Keywords:
Analgesics/pharmacology
;
Animals
;
Binding Sites
;
Binding, Competitive
;
Cell Line
;
Computer Simulation
;
Cyclohexanes/chemistry/*metabolism/*pharmacology
;
Drug Evaluation, Preclinical/*methods
;
Enzyme-Linked Immunosorbent Assay
;
G-Protein-Coupled Receptor Kinase 2
;
GTP-Binding Protein alpha Subunits/metabolism
;
GTP-Binding Protein beta Subunits/chemistry/*metabolism
;
GTP-Binding Protein gamma Subunits/chemistry/*metabolism
;
HL-60 Cells
;
Humans
;
Isoenzymes/metabolism
;
Mice
;
Mice, Inbred ICR
;
Mitogen-Activated Protein Kinases/metabolism
;
Molecular Structure
;
Morphine/pharmacology
;
N-Formylmethionine Leucyl-Phenylalanine/metabolism
;
Peptide Library
;
Peptides/*metabolism
;
Phosphatidylinositol 3-Kinases/metabolism
;
Phospholipase C beta
;
Protein Binding
;
Protein Interaction Mapping
;
*Signal Transduction
;
Software
;
Structure-Activity Relationship
;
Type C Phospholipases/metabolism
;
Xanthenes/chemistry/*metabolism/*pharmacology
;
beta-Adrenergic Receptor Kinases/metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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