Identification of quinoline-based compounds with dual activity against CysLT1R and GPBAR1 for the treatment of metabolic fatty liver disease

Pharmacological therapy based on dual receptor modulators represents an attractive opportunity for the modulation of the same cellular process by acting on different pathways. This study presents the discovery of new ligands with dual activity against the two membrane receptors, the cysteinyl leukotriene receptor 1 (CysLT1R) and the G-protein coupled bile acid receptor 1 (GPBAR1). The new series with quinoline scaffold has been designed starting from the structure of REV5901 - the first reported dual compound - with therapeutic potential in the treatment of colitis and other inflammatory processes. Computational studies, including molecular docking, molecular dynamics (MD), and metadynamics (MetaD) simulations, followed by biological assays, clarified the binding mode of the two most active compounds in the two GPCRs receptors, underlining the unprecedented structural basis for future drug design studies.