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 2021 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. application/pdf https://susi.usi.ch/global/documents/328336 https://localhost:5000/ark:/12658/srd1328336 https://susi.usi.ch/documents/328336/files/Conflitti_2021_jmedchem.pdf eng info:eu-repo/semantics/altIdentifier/doi/10.1021/acs.jmedchem.1c01078 info:eu-repo/semantics/altIdentifier/ark/12658/srd1328336 info:eu-repo/semantics/openAccess Rights reserved Journal of Medicinal Chemistry. - 2021, vol. 64, no. 22, p. 16512-16529 Binding modes Chemical calculations Ligands Quinolines Receptors info:eu-repo/classification/udc/61 Structural basis for developing multitarget compounds acting on Cysteinyl Leukotriene Receptor 1 and G-Protein coupled Bile Acid Receptor 1 http://purl.org/coar/resource_type/c_6501