Indol-1-yl Acetic Acids as Peroxisome Proliferator-Activated Receptor Agonists:  Design, Synthesis, Structural Biology, and Molecular Docking Studies

Abstract

A series of novel indole-based PPAR agonists is described leading to discovery of 10k, a highly potent PPAR pan-agonist. The structural biology and molecular docking studies revealed that the distances between the acidic group and the linker, when a ligand was complexed with PPARgamma protein, were important for the potent activity. The hydrophobic tail part of 10k makes intensive hydrophobic interaction with the PPARgamma protein resulting in potent activity.

Ajulemic Acid, a Synthetic Nonpsychoactive Cannabinoid Acid, Bound to the Ligand Binding Domain of the Human Peroxisome Proliferator-activated Receptor γ

“…Overall, 34 crystallographically independent LBD structures were compared by treating the subunits independently, when more than one LBD molecule is present in the asymmetric unit. Besides monomers A and B of the AJA complex described here, the following molecules were included: 1K74 (2), 1I7I (3), 2PRG (6), 3PRG (7) (53), and 1ZEO (54).…”

Virtual Screening for PPAR Modulators Using a Probabilistic Neural Network

“…of the receptor pocket ( Figure 6). Studies with ligand 14 revealed that the distance between the acid group and the linker were important for receptor activation, [31] which is also supported by the experimentally determined binding mode of rosiglitazone 13 (PDB code 2PRG, not shown). [33] The docking solutions suggest, however, that ligand 7 does not form a Ushape around helix 3 and extend to the activation function helix AF-2 (Tyr 473), which could explain its comparably low potency.…”

“…[29,30] We chose this receptor structure because it contains a large indole-based ligand 14 (PPARg: EC 50 = 70 nm; PPARa: EC 50 = 8 nm) that lacks the TZD group [31] and thus provides a reference structure for the comparably large binding pocket of PPARg ( % 1400 3 in apo-PPARg) [32] without providing a preformed TZD binding moiety. For the docking experiment, the binding pocket was defined by a radius of 5 around ligand 14.…”

Structural Basis for the Improved Potency of Peroxisome Proliferator‐Activated Receptor (PPAR) Agonists

“…Commercially available 5-hydroxyindole was O-alkylated with 1-bromo-3-chloropropane under basic conditions, yielding 22. [14] Further O-alkylation of 4-phenylbenzophenone (tail part B) with compound 22 gave the intermediate 23. The desired acid 15 was obtained by N-alkylation of 23 with methyl-2-bromoacetate under basic conditions, followed by ester hydrolysis with lithium hydroxide.…”

“…Moreover, the PPARg binding affinities as measured by scintillation proximity assay (SPA) also revealed that compound 15 showed stronger PPARg binding, with an IC 50 of 27 nm, than compound 10 (IC 50 = 50 nm). [14] To understand the difference in the activity level, we compared co-crystal structures of 15 with 10 ( Figure 3 a). Superimposition of 15 with 10 revealed, surprisingly, that the head part and the linker of these two ligands adopt different conformations and occupy different binding positions despite having the same chemical structure.…”