Dataset Information

Computational and Experimental Druggability Assessment of Human DNA Glycosylases.

ABSTRACT: Due to a polar or even charged binding interface, DNA-binding proteins are considered extraordinarily difficult targets for development of small-molecule ligands and only a handful of proteins have been targeted successfully to date. Recently, however, it has been shown that development of selective and efficient inhibitors of 8-oxoguanine DNA glycosylase is possible. Here, we describe the initial druggability assessment of DNA glycosylases in a computational setting and experimentally investigate several methods to target endonuclease VIII-like 1 (NEIL1) with small-molecule inhibitors. We find that DNA glycosylases exhibit good predicted druggability in both DNA-bound and -unbound states. Furthermore, we find catalytic sites to be highly flexible, allowing for a range of interactions and binding partners. One flexible catalytic site was rationalized for NEIL1 and further investigated experimentally using both a biochemical assay in the presence of DNA and a thermal shift assay in the absence of DNA.

SUBMITTER: Michel M

PROVIDER: S-EPMC6682003 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Computational and Experimental Druggability Assessment of Human DNA Glycosylases.

Michel Maurice M Visnes Torkild T Homan Evert J EJ Seashore-Ludlow Brinton B Hedenström Mattias M Wiita Elisée E Vallin Karl K Paulin Cynthia B J CBJ Zhang Jiaxi J Wallner Olov O Scobie Martin M Schmidt Andreas A Jenmalm-Jensen Annika A Warpman Berglund Ulrika U Helleday Thomas T

ACS omega 20190705 7

Due to a polar or even charged binding interface, DNA-binding proteins are considered extraordinarily difficult targets for development of small-molecule ligands and only a handful of proteins have been targeted successfully to date. Recently, however, it has been shown that development of selective and efficient inhibitors of 8-oxoguanine DNA glycosylase is possible. Here, we describe the initial druggability assessment of DNA glycosylases in a computational setting and experimentally investiga ...[more]

PMID: 31460271

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Project description:PurposeComputational models are widely used during the design and characterization of microwave ablation (MWA) devices, and have been proposed for pretreatment planning. Our objective was to assess three-dimensional (3D) transient temperature and ablation profiles predicted by MWA computational models with temperature profiles measured experimentally using magnetic resonance (MR) thermometry in ex vivo bovine liver.Materials and methodsWe performed MWA in ex vivo tissue under MR guidance using a custom, 2.45 GHz water-cooled applicator. MR thermometry data were acquired for 2 min prior to heating, during 5-10 min microwave exposures, and for 3 min following heating. Fiber-optic temperature sensors were used to validate the accuracy of MR temperature measurements. A total of 13 ablation experiments were conducted using 30-50 W applied power at the applicator input. MWA computational models were implemented using the finite element method, and incorporated temperature-dependent changes in tissue physical properties. Model-predicted ablation zone extents were compared against MRI-derived Arrhenius thermal damage maps using the Dice similarity coefficient (DSC).ResultsPrior to heating, the observed standard deviation of MR temperature data was in the range of 0.3-0.7°C. Mean absolute error between MR temperature measurements and fiber-optic temperature probes during heating was in the range of 0.5-2.8°C. The mean DSC between model-predicted ablation zones and MRI-derived Arrhenius thermal damage maps for 13 experimental set-ups was 0.95. When comparing simulated and experimentally (i.e. using MRI) measured temperatures, the mean absolute error (MAE %) relative to maximum temperature change was in the range 5%-8.5%.ConclusionWe developed a system for characterizing 3D transient temperature and ablation profiles with MR thermometry during MWA in ex vivo liver tissue, and applied the system for experimental validation of MWA computational models.

Dataset Information

Computational and Experimental Druggability Assessment of Human DNA Glycosylases.

Publications

Computational and Experimental Druggability Assessment of Human DNA Glycosylases.

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