Structural review of PPARγ in complex with ligands: Cartesian- and dihedral angle principal component analyses of X-ray crystallographic data.

Two decades of research into the ligand-dependent modulation of the activity of the peroxisome proliferator-activated receptor γ (PPARγ) have demonstrated the heterogeneous modes of action of PPARγ ligands, in terms of their interaction surfaces in the ligand-binding pocket, binding stoichiometry and ability to interact with functionally important parts of the receptor, through both direct and allosteric mechanisms. These findings signal the complex mechanistic bases of the distinct biological effects of different classes of PPARγ ligands. Today, the development of PPARγ ligands focuses on partial- and non-agonists as opposed to classical agonists, due to the severe side effects observed with PPARγ classical agonists as therapeutic agents. To aid this development, we performed principal component analyses of the atomic (Cartesian) coordinates (cPCA) and dihedral angles (dPCA) of the structures of human PPARγ from X-ray crystallography, available in the public domain, seeking to reveal ligand-induced trends. In the cPCA, projections of the structures along the principal components (PCs) demonstrated a moderate correlation between cPC1 and structural parameters related to the stabilization of helix 12, which is central to the transcriptional activation by PPARγ classical agonists. Consequently, the presented cPCA mapping of the PPARγ-ligand complexes may guide in silico drug discovery programs seeking to avoid stabilization of helix 12 in their development of partial- and non-agonistic PPARγ ligands. Notably, while the dPCA could identify key regions of dihedral fluctuation in the structural ensemble, the distributions along dPC1 - 2 could not be classified according to the same parameters as the distribution along cPC1. Proteins 2017; 85:1684-1698. © 2017 Wiley Periodicals, Inc.

Synthesis of 5-trifluoromethyl-2-sulfonylpyridine PPARß/δ antagonists: Effects on the affinity and selectivity towards PPARß/δ.

The covalent modification of peroxisome-proliferator activated receptor ß/δ (PPARß/δ) is part of the mode of action of 5-trifluoromethyl-2-sulfonylpyridine PPARß/δ antagonists such as GSK3787 and CC618. Herein, the synthesis and in vitro biological evaluation of a range of structural analogues of the two antagonists are reported. The new ligands demonstrate that an improvement in the selectivity of 5-trifluoromethyl-2-sulfonylpyridine antagonists towards PPARß/δ is achievable at the expense of their immediate affinity for PPARß/δ. However, their putatively covalent and irreversible mode of action may ensure their efficacy over time, as observed in time-resolved fluorescence resonance energy transfer (TR-FRET)-based ligand displacement assays.

A solid-state oxidation of 1,1,3,3-tetramethylguanidinium 4-methylbenzenesulfinate to 1,1,3,3-tetramethylguanidinium 4-methylbenzenesulfonate.

The organic acid-base complex 1,1,3,3-tetramethylguanidinium 4-methylbenzenesulfonate, C5H14N3(+)·C7H7O3S(-), was obtained from the corresponding 1,1,3,3-tetramethylguanidinium 4-methylbenzenesulfinate complex, C5H14N3(+)·C7H7O2S(-), by solid-state oxidation in air. Comparison of the two crystal structures reveals similar packing arrangements in the monoclinic space group P2(1)/c, with centrosymmetric 2:2 tetramers being connected by four strong N-H···O=S hydrogen bonds between the imine N atoms of two 1,1,3,3-tetramethylguanidinium bases and the O atoms of two acid molecules.

1,4-Bis(2-diazo-acet-yl)piperazine.

The asymmetric unit of the title compound, C8H10N6O2, contains one-half mol-ecule, which is completed by a crystallographic center of symmetry. The piperazine ring adopts a chair conformation. In the crystal, weak C-H⋯O inter-actions link the mol-ecules into layers parallel to the bc plane. The crystal packing also exhibits short N⋯N contacts of 3.0467 (16) Šbetween the terminal diazo N atoms from neighbouring mol-ecules.

α-Bromodiazoacetamides - a new class of diazo compounds for catalyst-free, ambient temperature intramolecular C-H insertion reactions.

In this work, we introduce a new class of halodiazocarbonyl compounds, α-halodiazoacetamides, which through a metal-free, ambient-temperature thermolysis perform intramolecular C-H insertions to produce α-halo-ß-lactams. When carried out with α-bromodiazoacetamides bearing cyclic side chains, the thermolysis reaction affords bicyclic α-halo-ß-lactams, in some cases in excellent yields, depending on the ring size and substitution pattern of the cyclic amide side chains.

Calculations of Absolute Solvation Free Energies with Transformato─Application to the FreeSolv Database Using the CGenFF Force Field.

We recently introduced transformato, an open-source Python package for the automated setup of large-scale calculations of relative solvation and binding free energy differences. Here, we extend the capabilities of transformato to the calculation of absolute solvation free energy differences. After careful validation against the literature results and reference calculations with the PERT module of CHARMM, we used transformato to compute absolute solvation free energies for most molecules in the FreeSolv database (621 out of 642). The force field parameters were obtained with the program cgenff (v2.5.1), which derives missing parameters from the CHARMM general force field (CGenFF v4.6). A long-range correction for the Lennard-Jones interactions was added to all computed solvation free energies. The mean absolute error compared to the experimental data is 1.12 kcal/mol. Our results allow a detailed comparison between the AMBER and CHARMM general force fields and provide a more in-depth understanding of the capabilities and limitations of the CGenFF small molecule parameters.

2-Diazo-1-(1,1-dioxothio-morpholin-4-yl)ethanone.

In the mol-ecule of the title compound, C(6)H(9)N(3)O(3)S, at 105 K, the six-membered ring is predominantly found in the chair conformation, with 1.89 (14)% in the boat conformation. In the crystal structure, there are five inter-molecular C-H⋯O=C and C-H⋯O=S contacts less than 2.6 Å, as well as a weak C-H⋯N=N inter-action to the diazo group.

tert-Butyl 4-(2-diazo-acet-yl)piperazine-1-carboxyl-ate.

The title crystal structure, C(11)H(18)N(4)O(3), is the first diazo-acetamide in which the diazo-acetyl group is attached to an N atom. The piperazine ring is in a chair form and hence the mol-ecule has an extended conformation. Both ring N atoms are bonded in an essentially planar configuration with the sum of the C-N-C angles being 359.8 (2) and 357.7 (2)°. In the crystal structure, the O atom of the diazo-acetyl group accepts two H atoms from C-H donors, thus generating chains of weak hydrogen-bonded R(2) (1)(7) rings.

The PPAR Ω Pocket: Renewed Opportunities for Drug Development.

The past decade of PPARγ research has dramatically improved our understanding of the structural and mechanistic bases for the diverging physiological effects of different classes of PPARγ ligands. The discoveries that lie at the heart of these developments have enabled the design of a new class of PPARγ ligands, capable of isolating central therapeutic effects of PPARγ modulation, while displaying markedly lower toxicities than previous generations of PPARγ ligands. This review examines the emerging framework around the design of these ligands and seeks to unite its principles with the development of new classes of ligands for PPARα and PPARß/δ. The focus is on the relationships between the binding modes of ligands, their influence on PPAR posttranslational modifications, and gene expression patterns. Specifically, we encourage the design and study of ligands that primarily bind to the Ω pockets of PPARα and PPARß/δ. In support of this development, we highlight already reported ligands that if studied in the context of this new framework may further our understanding of the gene programs regulated by PPARα and PPARß/δ. Moreover, recently developed pharmacological tools that can be utilized in the search for ligands with new binding modes are also presented.

(2SR,3RS)-Benz-yl[4-chloro-1-(4-chloro-phen-yl)-1-methoxy-carbon-yl-2-but-yl]-ammonium chloride.

In the racemic hydro-chloride salt of the title ester, C(19)H(22)Cl(2)NO(2) (+)·Cl(-), the penta-noic acid chain shows a mixture of trans and gauche orientations to give an overall helical conformation. The dihedral angle between the two aromatic rings is 26.11 (10)°. The charged secondary amine function participates in two N-H⋯Cl hydrogen bonds.

Synthesis, biological evaluation and molecular modeling studies of the PPARß/δ antagonist CC618.

Herein, we describe the synthesis, biological evaluation and molecular docking of the selective PPARß/δ antagonist (4-methyl-2-(4-(trifluoromethyl)phenyl)-N-(2-(5-(trifluoromethyl)-pyridin-2-ylsulfonyl)ethyl)thiazole-5-carboxamide)), CC618. Results from in vitro luciferase reporter gene assays against the three known human PPAR subtypes revealed that CC618 selectively antagonizes agonist-induced PPARß/δ activity with an IC50 = 10.0 µM. As observed by LC-MS/MS analysis of tryptic digests, the treatment of PPARß/δ with CC618 leads to a covalent modification of Cys249, located centrally in the PPARß/δ ligand binding pocket, corresponding to the conversion of its thiol moiety to a 5-trifluoromethyl-2-pyridylthioether. Finally, molecular docking is employed to shed light on the mode of action of the antagonist and its structural consequences for the PPARß/δ ligand binding pocket.