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

Abstract

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.

Evaluation of Urtica dioica Phytochemicals against Therapeutic Targets of Allergic Rhinitis Using Computational Studies

“…However, CRTH2 stands apart as it operates without conventional activation [41,61]. Molecular dynamics studies have revealed consistent transmembrane conformations among antagonists, agonists, and CRTH2 alone [41,58,62], except for the behavior of helix 8 [61,62]. This helix, upon binding of an agonist, will undergo compaction to inhibit arrestin recruitment.…”

“…Intracellular: The only known structural change is that the agonist causes helix 8 to undergo compaction, inhibiting arrestin recruitment [61,62].…”

“…As mentioned above, the only identified structural change was the agonist-induced compaction of helix 8. [61,62]. During the MD simulation, most transmembrane segments remained unaltered.…”

Ramatroban-Based Analogues Containing Fluorine Group as Potential 18F-Labeled Positron Emission Tomography (PET) G-Protein Coupled Receptor 44 (GPR44) Tracers

“…The binding affinity for GPR44, estimated through a MM/PBSA-based approach, showed total free energy values of -67.50 kcal/mol for CT-133 and -50.12 kcal/mol for PGD 2 . The lower binding energy has been attributed to the 7-azaindole group that causes CT-133 to bind more favorably to GPR44 than PGD 2 [ 89 ].…”