The design, synthesis, docking, and biological evaluation of novel potent HDAC3 and HDAC8 isoxazole- and pyrazole-based diazide probes suitable for Binding Ensemble Profiling with Photoaffinity Labeling (BEProFL) experiments in cells is described. Both the isoxazole- and pyrazole-based probes exhibit low nanomolar inhibitory activity against HDAC3 and HDAC8, respectively. The pyrazole-based probe 3f appears to be one of the most active HDAC8 inhibitors reported in the literature with an IC50 of 17 nM. Our docking studies suggest that unlike the isoxazole-based ligands the pyrazole-based ligands are flexible enough to occupy the second binding site of HDAC8. Probes/inhibitors 2b, 3a, 3c, and 3f exerted the anti-proliferative and neuroprotective activities at micromolar concentrations through inhibition of nuclear HDACs, indicating that they are cell permeable and the presence of an azide or a diazide group does not interfere with the neuroprotection properties, or enhance cellular cytotoxicity, or affect cell permeability.
Background: Human UDP-xylose synthase (hUXS1) is responsible for conversion of UDP-glucuronic acid to UDP-xylose.Results: Crystal structure, molecular dynamics simulations, and reaction course analysis give conclusive insight into the enzymatic mechanism in three catalytic steps.Conclusion: Distortion of sugar pyranose ring in bound substrate facilitates enzymatic reaction.Significance: A detailed mechanism for catalysis by hUXS1 is proposed.
A predictive model of the effect of crystal agglomeration on particle form and size distribution requires the quantification of various process parameters that depend on the microscopic properties of specific crystal faces and their interaction with the solvent. In this article, we discuss the various stages in the agglomeration process, using the results of recent experiments on breaking the agglomerative bond and atomic level simulations on the forces involved in crystal aggregation, to highlight the questions that need to be resolved for agglomeration processes to be understood.
Pantothenate synthetase (PS) is one of the potential new antimicrobial targets that may also be useful for the treatment of the nonreplicating persistent forms of Mycobacterium tuberculosis. In this Letter we present a series of 5- tert-butyl- N-pyrazol-4-yl-4,5,6,7-tetrahydrobenzo[ d]isoxazole-3-carboxamide derivatives as novel potent Mycobacterium tuberculosis PS inhibitors, their in silico molecular design, synthesis, and inhibitory activity.
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