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NMR studies of anion-induced conformational changes in diindolylureas and diindolylthioureas.

ABSTRACT: The conformational properties of 1,3-diindolylureas and thioureas were studied by a combination of heteronuclear NMR spectroscopy and quantum mechanics calculations. NOE experiments showed that the anti-anti conformer along the C7-N7? bonds was predominant in DMSO-d(6) solution in the absence of anions. Anion-induced changes in the (1)H and (15)N chemical shifts confirm the weak binding of chloride anions with negligible conformational changes. Strong deshielding of ureido protons and moderate deshielding of indole NH was observed upon the addition of acetate, benzoate, bicarbonate and dihydrogen phosphate, which indicated that the predominant hydrogen bond interactions occurred at the urea donor groups. Binding of oxo-anions caused conformational changes along the C7-N7? bonds and the syn-syn conformer was preferred for anion-receptor complexes. The conformational changes upon anion binding are in good agreement with energetic preferences established by ab initio calculations.

SUBMITTER: Makuc D

PROVIDER: S-EPMC3182429 | biostudies-other | 2011

REPOSITORIES: biostudies-other

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NMR studies of anion-induced conformational changes in diindolylureas and diindolylthioureas.

Makuc Damjan D Hiscock Jennifer R JR Light Mark E ME Gale Philip A PA Plavec Janez J

Beilstein journal of organic chemistry 20110902

The conformational properties of 1,3-diindolylureas and thioureas were studied by a combination of heteronuclear NMR spectroscopy and quantum mechanics calculations. NOE experiments showed that the anti-anti conformer along the C7-N7α bonds was predominant in DMSO-d(6) solution in the absence of anions. Anion-induced changes in the (1)H and (15)N chemical shifts confirm the weak binding of chloride anions with negligible conformational changes. Strong deshielding of ureido protons and moderate d ...[more]

PMID: 21977204

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Project description:Protein-protein interactions represent difficult but increasingly important targets for the design of therapeutic compounds able to interfere with biological processes. Recently, fragment-based strategies have been proposed as attractive approaches for the elaboration of protein-protein surface inhibitors from fragment-like molecules. One major challenge in targeting protein-protein interactions is related to the structural adaptation of the protein surface upon molecular recognition. Methods capable of identifying subtle conformational changes of proteins upon fragment binding are therefore required at the early steps of the drug design process. In this report we present a fast NMR method able to probe subtle conformational changes upon fragment binding. The approach relies on the comparison of experimental fragment-induced Chemical Shift Perturbation (CSP) of amine protons to CSP simulated for a set of docked fragment poses, considering the ring-current effect from fragment binding. We illustrate the method by the retrospective analysis of the complex between the anti-apoptotic Bcl-xL protein and the fragment 4'-fluoro-[1,1'-biphenyl]-4-carboxylic acid that was previously shown to bind one of the Bcl-xL hot spots. The CSP-based approach shows that the protein undergoes a subtle conformational rearrangement upon interaction, for residues located in helices [Formula: see text]2, [Formula: see text]3 and the very beginning of [Formula: see text]5. Our observations are corroborated by residual dipolar coupling measurements performed on the free and fragment-bound forms of the Bcl-xL protein. These NMR-based results are in total agreement with previous molecular dynamic calculations that evidenced a high flexibility of Bcl-xL around the binding site. Here we show that CSP of protein amine protons are useful and reliable structural probes. Therefore, we propose to use CSP simulation to assess protein conformational changes upon ligand binding in the fragment-based drug design approach.

Dataset Information

NMR studies of anion-induced conformational changes in diindolylureas and diindolylthioureas.

Publications

NMR studies of anion-induced conformational changes in diindolylureas and diindolylthioureas.

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