Structural basis for developing multitarget compounds acting on Cysteinyl Leukotriene Receptor 1 and G-Protein coupled Bile Acid Receptor 1
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Fiorillo, Bianca
Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
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Sepe, Valentina
Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
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Conflitti, Paolo
Euler Institute (EUL), Università della Svizzera italiana, Switzerland
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Roselli, Rosalinda
Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
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Biagioli, Michele
Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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Marchianò, Silvia
Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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De Luca, Pasquale
Head – Sequencing and Molecular Analyses Center, RIMAR Stazione Zoologica, Naples, Italy
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Baronissi, Giuliana
Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
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Rapacciuolo, Pasquale
Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
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Cassiano, Chiara
Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
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Catalanotti, Bruno
Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
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Zampella, Angela
Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
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Limongelli, Vittorio
Department of Pharmacy, University of Naples “Federico II”, Naples, Italy ; Euler Institute (EUL), Università della Svizzera italiana, Switzerland
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Fiorucci, Stefano
Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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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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Medicine
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green
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https://n2t.net/ark:/12658/srd1328336
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