Publications by authors named "S Margosiak"
A novel method for applying high-throughput docking to challenging metalloenzyme targets is described. The method utilizes information-based virtual transformation of library carboxylates to hydroxamic acids prior to docking, followed by compound acquisition, one-pot (two steps) chemical synthesis and in vitro screening. In two experiments targeting the botulinum neurotoxin serotype A metalloprotease light chain, hit rates of 32% and 18% were observed.
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- Four core structures were studied for their ability to inhibit anthrax lethal factor (LF) while assessing toxicity, physicochemical properties, in vitro ADME profiles, and effectiveness in rat models.
- The phenoxyacetic acid series showed low efficacy in the rat model due to poor stability in rat microsomes and plasma.
- X-ray crystallography uncovered specific interactions that enhance the binding affinity of inhibitors with a secondary amine present in the C2-side chain.
Background: Dengue fever, dengue haemorrhagic fever, and dengue shock syndrome are caused by infections with any of the four serotypes of the dengue virus (DENV), and are an increasing global health risk. The related West Nile virus (WNV) causes significant morbidity and mortality as well, and continues to be a threat in endemic areas. Currently no FDA-approved vaccines or therapeutics are available to prevent or treat any of these infections.
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- Neurotoxins from Clostridium botulinum are highly toxic and pose a bioterrorism risk, driving research for small molecule inhibitors targeting their active sites.
- Studies have focused on the light chain zinc-dependent metalloprotease domain of the neurotoxin, with challenges due to its flexible active site.
- X-ray crystal structures reveal that binding of unique hydroxamate-based inhibitors significantly alters the active site, particularly a loop that undergoes substantial conformational changes, leading to a more compact and effective catalytic pocket.
New anthrax lethal factor inhibitors (LFIs) were designed based upon previously identified potent inhibitors 1a and 2. Combining the new core structures with modifications to the C2-side chain yielded analogs with improved efficacy in the rat lethal toxin model.
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