Same Target, Different Therapeutic Outcomes: The Case of CAY10471 and Fevipiprant on CRTh2 Receptor in Treatment of Allergic Rhinitis and Asthma.

Abstract

OBJECTIVE:

Prostaglandin 2 (PGD2) mediated signalling of Chemoattractant Receptorhomologous molecule expressed on Th2 cells (CRTh2) receptor has been implicated in the recruitment of inflammatory cells. This explains the design of highly selective compounds with innate abilities to antagonize PGD2-CRTh2 interactions and prevent pro-inflammatory allergies such as rhinitis and uncontrolled asthma. The development of PGD2-competitive CRTh2 binders; CAY10471 and Fevipiprant represent remarkable therapeutic progress even though they elicit disparate pharmacological propensities despite utilizing the same binding pocket.

METHODS & RESULTS:

In this study, we seek to pinpoint the underlying phenomenon associated with differential CRTh2 therapeutic inhibition by CAY10471 and Fevipiprant using membraneembedded molecular dynamics simulation. Findings revealed that the common carboxylate group of both compounds elicited strong attractive charges with active site Arg170 and Lys210. Interestingly, a distinctive feature was the steady occurrence of high-affinity salt-bridges and an Arg170-mediated pi-cation interaction with the tetrahydrocarbozole ring of CAY10471. Further investigations into the active site motions of both ligands revealed that CAY10471 was relatively more stable. Comparative binding analyses also revealed that CAY10471 exhibited higher ΔG, indicating the cruciality of the ring stabilization role mediated by Arg170. Moreover, conformational analyses revealed that the inhibitory activity of CAY10471 was more prominent on CRTh2 compared to Fevipiprant.

CONCLUSIONS:

These findings could further advance the strategic design of novel CRTh2 binders in the treatment of diseases related to pro-inflammatory allergies.

• Authors: Abdul R Issahaku, Clement Agoni, Opeyemi S Soremekun, Patrick A Kubi, Ransford O Kumi, Fisayo A Olotu, Mahmoud E S Soliman
• Journal: Combinatorial chemistry & high throughput screening (Comb Chem High Throughput Screen) Vol. 22 Issue 8 Pg. 521-533 ( 2019) ISSN: 1875-5402 [Electronic] United Arab Emirates
• PMID: 31538888 (Publication Type: Journal Article)
• Copyright: Copyright© Bentham Science Publishers; For any queries, please email at [email protected].

Chemical References

• CAY 10471
• Carbazoles
• Indoleacetic Acids
• Pyridines
• Receptors, Immunologic
• Receptors, Prostaglandin
• Sulfonamides
• fevipiprant
• prostaglandin D2 receptor

Topics

• Asthma (drug therapy, metabolism)
• Carbazoles (chemistry, pharmacology)
• High-Throughput Screening Assays
• Humans
• Indoleacetic Acids (chemistry, pharmacology)
• Molecular Dynamics Simulation
• Molecular Structure
• Pyridines (chemistry, pharmacology)
• Receptors, Immunologic (antagonists & inhibitors, metabolism)
• Receptors, Prostaglandin (antagonists & inhibitors, metabolism)
• Rhinitis, Allergic (drug therapy, metabolism)
• Sulfonamides (chemistry, pharmacology)
• Treatment Outcome