Title:Same Target, Different Therapeutic Outcomes: The Case of CAY10471 and Fevipiprant on CRTh2 Receptor in Treatment of Allergic Rhinitis and Asthma
VOLUME: 22 ISSUE: 8
Author(s):Abdul R. Issahaku, Clement Agoni, Opeyemi S. Soremekun, Patrick A. Kubi, Ransford O. Kumi, Fisayo A. Olotu and Mahmoud E.S. Soliman*
Affiliation:Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001
Keywords:Chemoattractant Receptor-homologous molecule expressed on Th2 cells (CRTh2), allergic rhinitis, asthma, PGD2
antagonists, CAY10471, Fevipiprant, PGD2-CRTh2 signaling, type 2 inflammation.
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.
