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.