Unbinding pathways from the glucocorticoid receptor shed light on the reduced sensitivity of glucocorticoid ligands to a naturally occurring, clinically relevant mutant receptor.

Glucocorticoids are endogenous steroid hormones that regulate essential biological functions, including metabolism, growth, and apoptosis. Glucocorticoids represent the most effective anti-inflammatory agents for the treatment of several inflammatory conditions. However, the clinical use of such drugs is hampered by severe side effects.

Molecular dynamics simulation of the heterodimeric mGluR2/5HT(2A) complex. An atomistic resolution study of a potential new target in psychiatric conditions.

Homo- and heterodimerization is becoming an assessed concept in G-protein coupled receptor (GPCR) pharmacology, and the notion that GPCRs may dimerize or oligomerize is allowing for a reinterpretation of some inconsistencies or anomalies and is providing medicinal chemists with potentially relevant novel molecular targets for a variety of therapeutic conditions. Recently, it has been reported that two unrelated GPCRs, namely class C metabotropic glutamate receptor type-2 (mGluR2) and class A 5HT(2A) serotoninergic receptor, can heterodimerize at the transmembrane domain level. We performed a 40 ns molecular dynamics simulation of the mGluR2/5HT(2A) heterocomplex constructed around a TM4/TM5 interface and embedded in an explicit phospholipidic bilayer surrounded by water molecules.

1H, 13C NMR, X-ray and conformational studies of new 1-alkyl-3-benzoyl-pyrazole and 1-alkyl-3-benzoyl-pyrazoline derivatives.

The (1)H and (13)C NMR resonances of 22 1-alkyl-pyrazole and 25 1-alkyl-pyrazoline derivatives were assigned completely using the concerted application of one- and two-dimensional experiments (DEPT, gs-HMQC and gs-HMBC). Nuclear Overhauser enhancement (NOE) effects, conformational analysis and X-ray crystallography confirm the preferred conformation of those compounds.

Back door modulation of the farnesoid X receptor: design, synthesis, and biological evaluation of a series of side chain modified chenodeoxycholic acid derivatives.

Carbamate derivatives of bile acids were synthesized with the aim of systematically exploring the potential for farnesoid X receptor (FXR) modulation endowed with occupancy of the receptor's back door, localized between loops H1-H2 and H4-H5. Since it was previously shown that bile acids bind to FXR by projecting the carboxylic tail opposite the transactivation function 2 (AF-2, helix 12), functionalization of the side chain is not expected to interfere directly with the orientation of H12 but can result in a more indirect way of receptor modulation. The newly synthesized compounds were extensively characterized for their ability to modulate FXR function in a variety of assays, including the cell-free fluorescence resonance energy transfer (FRET) assay and the cell-based luciferase transactivation assay, and displayed a broad range of activity from full agonism to partial antagonism.

Molecular dynamics simulation of the ligand binding domain of farnesoid X receptor. Insights into helix-12 stability and coactivator peptide stabilization in response to agonist binding.

The dynamic changes which take place in the ligand binding domain (LBD) of farneosid X receptor (FXR) in response to agonist binding and in the presence of coactivator peptides were studied with nanosecond time-scale molecular dynamics. Four different systems were analyzed, including the holo-LBD complexed with 6ECDCA, the holo-LBD in the presence of two coactivator peptides, and two artificial apo forms, with and without coactivator peptides. Our results revealed a detailed picture of the differential micro- and macromodifications occurring in the LBD in the presence or not of the agonist molecule and the coactivator peptides.

Binding mode of 6ECDCA, a potent bile acid agonist of the farnesoid X receptor (FXR).

Based on the folding conservation across the nuclear receptor superfamily and the sequence homology with RAR-gamma, we report the construction of a three dimensional model of the ligand binding domain of FXR. The model is exploited for the elucidation of the binding mode of 6alpha-ethyl-chenodeoxycholic acid. The results of the docking experiments give quite clear indications that the bile acid derivative would bind the receptor in a mode significantly different than that observed for agonists of other nuclear receptor superfamily.

Design, synthesis, and biological activity of hybrid compounds between uramustine and DNA minor groove binder distamycin A.

The design, synthesis, characterization, DNA binding properties, and cytotoxic activity of a novel series of hybrids, namely, a molecular combination of the natural antibiotic distamycin A and the antineoplastic agent uramustine, are reported, and the structure-activity relationships are discussed. This homologous series 29-34 consisted of the minor groove binder distamycin A joined to uramustine (uracil mustard) by suitable aliphatic carboxylic acid moieties containing a flexible polymethylene chain that is variable in length [(CH(2))(n)(), where n = 1-6). All the hybrid compounds in this series exhibit enhanced activity compared to both distamycin A and uramustine derivatives 22-27 used for conjugation, giving IC(50) values in the range 7.