Lipid-Embedded Molecular Dynamics Simulation Model for Exploring the Reverse Prostaglandin D2 Agonism of CT-133 towards CRTH2 in the Treatment of Type-2 Inflammation Dependent Diseases.
CT-133
PGD2 antagonists
chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2)
molecular dynamics simulation
prostaglandin d2
reverse agonism
Journal
Chemistry & biodiversity
ISSN: 1612-1880
Titre abrégé: Chem Biodivers
Pays: Switzerland
ID NLM: 101197449
Informations de publication
Date de publication:
Mar 2020
Mar 2020
Historique:
received:
01
10
2019
accepted:
07
02
2020
pubmed:
9
2
2020
medline:
26
5
2021
entrez:
9
2
2020
Statut:
ppublish
Résumé
Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) has been involved in several inflammation dependent diseases by mediating the chemotaxis of pro-inflammatory cells in response to allergy and other responses through PGD2 ligation. This CRTH2-PGD2 signaling pathway has become a target for treating allergic and type 2 inflammation dependent diseases, with many inhibitors developed to target the PGD2 binding pocket. One of such inhibitors is the ramatroban analog, CT-133, which exhibited therapeutic potency cigarette smoke-induced acute lung injury in patients. Nonetheless, the molecular mechanism and structural dynamics that accounts for its therapeutic prowess remain unclear. Employing computational tools, this study revealed that although the carboxylate moiety in CT-133 and the native agonist PGD2 aided in their stability within the CRTH2 binding pocket, the tetrahydrocarbazole group of CT-133 engaged in strong interactions with binding pocket residues which could have formed as the basis of the antagonistic advantage of CT-133. Tetrahydrocarbazole group interactions also enhanced the relative stability CT-133 within the binding pocket which consequently favored CT-133 binding affinity. CT-133 binding also induced an inactive or 'desensitized' state in the helix 8 of CRTH2 which could conversely favor the recruitment of arrestin. These revelations would aid in the speedy development of small molecule inhibitors of CRTH2 in the treatment of type 2 inflammation dependent diseases.
Identifiants
pubmed: 32034875
doi: 10.1002/cbdv.201900548
doi:
Substances chimiques
Boronic Acids
0
CRTH2 antagonist CT-133
0
Lipids
0
Prostaglandin D2
RXY07S6CZ2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1900548Informations de copyright
© 2020 Wiley-VHCA AG, Zurich, Switzerland.
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