Differential targeting of Gbetagamma-subunit signaling with small molecules.
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.
Bonacci
Tabetha M
TM
Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Mathews
Jennifer L
JL
Yuan
Chujun
C
Lehmann
David M
DM
Malik
Sundeep
S
Wu
Dianqing
D
Font
Jose L
JL
Bidlack
Jean M
JM
Smrcka
Alan V
AV
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002460:Cell Line; D003198:Computer Simulation; D003510:Cyclohexanes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004797:Enzyme-Linked Immunosorbent Assay; D054769:G-Protein-Coupled Receptor Kinase 2; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism; D044387:GTP-Binding Protein beta Subunits / Q000737:chemistry / Q000378:metabolism*; D044388:GTP-Binding Protein gamma Subunits / Q000737:chemistry / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015394:Molecular Structure; D009020:Morphine / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism; D019151:Peptide Library; D010455:Peptides / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D054799:Phospholipase C beta; D011485:Protein Binding; D025941:Protein Interaction Mapping; D015398:Signal Transduction; D012984:Software; D013329:Structure-Activity Relationship; D010738:Type C Phospholipases / Q000378:metabolism; D014966:Xanthenes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D051552:beta-Adrenergic Receptor Kinases / Q000378:metabolism
D000700:Analgesics; D003510:Cyclohexanes; D044385:GTP-Binding Protein alpha Subunits; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D007527:Isoenzymes; C509953:M119 compound; D019151:Peptide Library; D010455:Peptides; D014966:Xanthenes; D009240:N-Formylmethionine Leucyl-Phenylalanine; D009020:Morphine; D019869:Phosphatidylinositol 3-Kinases; C496567:GRK2 protein, human; D051552:beta-Adrenergic Receptor Kinases; D054769:G-Protein-Coupled Receptor Kinase 2; D020928:Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; D054799:Phospholipase C beta