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

Abstract

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 (CysLT 1 R) and Gprotein-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 Arg79 2.60 of CysLT 1 R and achieve dual activity.

Discovery of a Potent and Orally Active Dual GPBAR1/CysLT1R Modulator for the Treatment of Metabolic Fatty Liver Disease

“…On the other hand, the binding mode elucidated by docking calculations performed in CysLT 1 R showed the quinoline portion of compounds 1–12 positioned in the pocket formed by TM3, TM4, and TM5. In both cases, the ligand binding mode agrees with that we have recently reported for a series of alpha-pentyl-3-[2-quinolinylmethoxy] benzyl alcohol - REV5901–derivatives ( Fiorillo et al, 2021 ). In the following section, we discuss in detail the binding mode of 2 that is the only dual-activity compound of the series and represents an interesting lead compound to achieve potent CysLT 1 R/GPBAR1 dual ligands.…”

“…Finally, the carboxy-terminal group forms a salt bridge interaction with Arg79 2.60 and two water-mediated H-bonds, one again with Arg79 2.60 and the other with Thr109 3.38 . Interestingly, the binding mode of compound 2 resembles the crystallographic binding pose of pranlukast, a potent antagonist of CysLT 1 R ( Luginina et al, 2019 ), which occupies the same region of the receptor and interacts similarly with the surrounding residues of the pocket, including the H-bond and salt bridge interactions with Arg79 2.60 ( Figure 3C ) ( Fiorillo et al, 2021 ).…”

“…Agonistic activities of compounds on GPBAR1 were compared to TLCA, which was set as 100%. All new compounds were screened in vitro for their CysLT 1 R antagonistic activity, as previously described ( Sarau et al, 1999 ; Fiorillo et al, 2021 ). Compounds 2 and 7–12 were demonstrated antagonists of the CysLT 1 R, with efficacies in the range 76–109% and as shown in Table 1 , the best results in terms of efficacy on both receptors were found in compound 2.…”

“…Following this general concept, we have recently envisaged in REV5901, a well-characterized CysLT 1 R antagonist, a privileged chemical scaffold for the development of dual CysLT 1 R antagonists/GPBAR1 agonists ( Biagioli et al, 2020b ), reporting the first family of derivatives improved in their synthetic accessibility and in their pharmacokinetic profiles ( Fiorillo et al, 2021 ).…”

“…Pursuing this strategy and exploring further modifications on REV5901s quinoline scaffold ( Figure 1 ), two sets of derivatives have been designed and synthetized by introducing a linker (rigid-biphenyl ring and flexible-alkyl chain) between the quinoline moiety and a polar or negatively charged end-group ( Figure 1 ), able to intercept, through a water molecule-mediated H-bond, Arg79 2.60 (superscripts refer to Ballesteros-Weinstein numbering) ( Ballesteros and Weinstein 1995 ) in CysLT 1 R ( Fiorillo et al, 2021 ), identifying several selective CysLT 1 R antagonists (compounds 7–12) and compound 2, a potent dual CysLT 1 R antagonist/GPBAR1 agonist, endowed with an excellent pharmacodynamic and pharmacokinetic profile. Assisted by a deep in vivo pharmacological evaluation, here we present, in a proof-of-concept study, the first evidence that dual modulation of CysLT 1 R/GPBAR1 represents a new armamentarium in NASH pharmacological treatment.…”