Structural basis for developing multitarget compounds acting on Cysteinyl Leukotriene Receptor 1 and G-Protein coupled Bile Acid Receptor 1

Fiorillo, Bianca; Sepe, Valentina; Conflitti, Paolo; Roselli, Rosalinda; Biagioli, Michele; Marchianò, Silvia; De Luca, Pasquale; Baronissi, Giuliana; Rapacciuolo, Pasquale; Cassiano, Chiara; Catalanotti, Bruno; Zampella, Angela; Limongelli, Vittorio; Fiorucci, Stefano

doi:10.1021/acs.jmedchem.1c01078

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Journal article

Structural basis for developing multitarget compounds acting on Cysteinyl Leukotriene Receptor 1 and G-Protein coupled Bile Acid Receptor 1

Fiorillo, Bianca Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
Sepe, Valentina Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
Conflitti, Paolo Euler Institute (EUL), Università della Svizzera italiana, Switzerland
Roselli, Rosalinda Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
Biagioli, Michele Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Marchianò, Silvia Department of Medicine and Surgery, University of Perugia, Perugia, Italy
De Luca, Pasquale Head – Sequencing and Molecular Analyses Center, RIMAR Stazione Zoologica, Naples, Italy
Baronissi, Giuliana Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
Rapacciuolo, Pasquale Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
Cassiano, Chiara Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
Catalanotti, Bruno Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
Zampella, Angela Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
Limongelli, Vittorio Department of Pharmacy, University of Naples “Federico II”, Naples, Italy ; Euler Institute (EUL), Università della Svizzera italiana, Switzerland
Fiorucci, Stefano Department of Medicine and Surgery, University of Perugia, Perugia, Italy

2021

Published in:

Journal of Medicinal Chemistry. - 2021, vol. 64, no. 22, p. 16512-16529

English G-protein-coupled receptors (GPCRs) are the molecular target of 40% of marketed drugs and the most investigated structures to develop novel therapeutics. Different members of the GPCRs superfamily can modulate the same cellular process acting on diverse pathways, thus representing an attractive opportunity to achieve multitarget drugs with synergic pharmacological effects. Here, we present a series of compounds with dual activity toward cysteinyl leukotriene receptor 1 (CysLT1R) and G-protein-coupled bile acid receptor 1 (GPBAR1). They are derivatives of REV5901─the first reported dual compound─with therapeutic potential in the treatment of colitis and other inflammatory processes. We report the binding mode of the most active compounds in the two GPCRs, revealing unprecedented structural basis for future drug design studies, including the presence of a polar group opportunely spaced from an aromatic ring in the ligand to interact with Arg792.60 of CysLT1R and achieve dual activity.

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