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

J Med Chem. 2021 Nov 25;64(22):16512-16529. doi: 10.1021/acs.jmedchem.1c01078. Epub 2021 Nov 12.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry*
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Colitis / drug therapy
  • Humans
  • Leukotriene D4 / pharmacology
  • Macrophages / drug effects
  • Mice
  • Molecular Docking Simulation
  • Protein Binding
  • RAW 264.7 Cells
  • Receptors, G-Protein-Coupled / drug effects*
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Leukotriene / drug effects*
  • Receptors, Leukotriene / metabolism
  • Structure-Activity Relationship


  • Anti-Inflammatory Agents, Non-Steroidal
  • GPBAR1 protein, human
  • Receptors, G-Protein-Coupled
  • Receptors, Leukotriene
  • Leukotriene D4
  • leukotriene D4 receptor