Structural Basis for Developing Multitarget Compounds Acting on Cysteinyl Leukotriene Receptor 1 and G‑Protein-Coupled Bile Acid Receptor 1

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.