107 research outputs found
Alien Registration- Boutin, Celanire (Winslow, Kennebec County)
https://digitalmaine.com/alien_docs/16354/thumbnail.jp
Allosteric modulation of metabotropic glutamate receptor 4 activates IDO1-dependent, immunoregulatory signaling in dendritic cells
Metabotropic glutamate receptor 4 (mGluR4) possesses immune modulatory properties in vivo, such that a positive allosteric modulator (PAM) of the receptor confers protection on mice with relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE). ADX88178 is a newly-developed, one such mGluR4 modulator with high selectivity, potency, and optimized pharmacokinetics. Here we found that application of ADX88178 in the RR-EAE model system converted disease into a form of mild-yet chronic-neuroinflammation that remained stable for over two months after discontinuing drug treatment. In vitro, ADX88178 modulated the cytokine secretion profile of dendritic cells (DCs), increasing production of tolerogenic IL-10 and TGF-β. The in vitro effects required activation of a Gi-independent, alternative signaling pathway that involved phosphatidylinositol-3-kinase (PI3K), Src kinase, and the signaling activity of indoleamine 2,3-dioxygenase 1 (IDO1). A PI3K inhibitor as well as small interfering RNA targeting Ido1-but not pertussis toxin, which affects Gi protein-dependent responses-abrogated the tolerogenic effects of ADX88178-conditioned DCs in vivo. Thus our data indicate that, in DCs, highly selective and potent mGluR4 PAMs such as ADX88178 may activate a Gi-independent, long-lived regulatory pathway that could be therapeutically exploited in chronic autoimmune diseases such as multiple sclerosis
Targeting type-2 metabotropic glutamate receptors to protect vulnerable hippocampal neurons against ischemic damage
DOGS: Reaction-Driven de novo Design of Bioactive Compounds
We present a computational method for the reaction-based de novo design of drug-like molecules. The software DOGS (Design of Genuine Structures) features a ligand-based strategy for automated ‘in silico’ assembly of potentially novel bioactive compounds. The quality of the designed compounds is assessed by a graph kernel method measuring their similarity to known bioactive reference ligands in terms of structural and pharmacophoric features. We implemented a deterministic compound construction procedure that explicitly considers compound synthesizability, based on a compilation of 25'144 readily available synthetic building blocks and 58 established reaction principles. This enables the software to suggest a synthesis route for each designed compound. Two prospective case studies are presented together with details on the algorithm and its implementation. De novo designed ligand candidates for the human histamine H4 receptor and γ-secretase were synthesized as suggested by the software. The computational approach proved to be suitable for scaffold-hopping from known ligands to novel chemotypes, and for generating bioactive molecules with drug-like properties
Alien Registration- Pauin, Celanire (Biddeford, York County)
https://digitalmaine.com/alien_docs/4644/thumbnail.jp
Alien Registration- Boisvert, Celanire (Biddeford, York County)
https://digitalmaine.com/alien_docs/2222/thumbnail.jp
Alien Registration- Labonte, Celanire (Winthrop, Kennebec County)
https://digitalmaine.com/alien_docs/16958/thumbnail.jp
Alien Registration- Boisvert, Celanire (Biddeford, York County)
https://digitalmaine.com/alien_docs/2222/thumbnail.jp
Alien Registration- Goulet, Marie Celanire (Biddeford, York County)
https://digitalmaine.com/alien_docs/5480/thumbnail.jp
Alien Registration- Pauin, Celanire (Biddeford, York County)
https://digitalmaine.com/alien_docs/4644/thumbnail.jp
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