A5101801769- Cholinesterase and Neurodegenerative Diseases
- Computational Drug Discovery Methods
- Ion Channels and Receptors
- Pesticide Exposure and Toxicity
- Neurobiology and Insect Physiology Research
- Phytochemicals and Antioxidant Activities
- Pharmacogenetics and Drug Metabolism
- Phosphodiesterase function and regulation
- Neuroscience and Neuropharmacology Research
- Insect and Pesticide Research
- Entomopathogenic Microorganisms in Pest Control
- Chemical synthesis and alkaloids
- Lipid Membrane Structure and Behavior
- Sulfur-Based Synthesis Techniques
- Click Chemistry and Applications
- Nicotinic Acetylcholine Receptors Study
- bioluminescence and chemiluminescence research
- Insect Pest Control Strategies
- Bee Products Chemical Analysis
- Microbial Natural Products and Biosynthesis
- Malaria Research and Control
- Ion channel regulation and function
- Insects and Parasite Interactions
- Photochromic and Fluorescence Chemistry
- Biochemical Analysis and Sensing Techniques
University of Defence
2019-2025
University Hospital Hradec Králové
2019-2025
Medical University of Graz
2015-2018
Johannes Kepler University of Linz
2014-2015
Tacrine (THA), a long withdrawn drug, is still popular scaffold used in medicinal chemistry, mainly for its good reactivity and multi-targeted effect. However, THA-associated hepatotoxicity an issue must be considered drug discovery based on the THA scaffold. Following our previously identified hit compound 7-phenoxytacrine (7-PhO-THA), we systematically explored chemical space with 30 novel derivatives, focus low hepatotoxicity, anticholinesterase action, antagonism at GluN1/GluN2B subtype...
Characterization of disease-associated Orai1 mutants reveals the multistep gating mechanism for CRAC channel.
The Ca(2+) release-activated channel mediates influx in a plethora of cell types, thereby controlling diverse cellular functions. complex is composed stromal interaction molecule 1 (STIM1), an endoplasmic reticulum Ca(2+)-sensing protein, and Orai1, plasma membrane channel. Channels STIM1 Orai1 mediate even at low extracellular concentrations. We investigated whether the activity adapted to different environmental used homology modeling molecular dynamics simulations predict presence...
Alzheimer’s disease (AD) is a complex neurodegenerative disorder with an unclear etiology. Current treatments, primarily cholinesterase (ChE) inhibitors and N-methyl-D-aspartate receptor (NMDAR) antagonists, offer only symptomatic relief. Drugs targeting one pathological condition have generated limited efficacy. Thus, combining two or more therapeutic interventions into molecule believed to provide higher benefits for the treatment of AD. In this study, we designed, synthesized,...
Tacrine was the first drug to be approved for Alzheimer’s disease (AD) treatment, acting as a cholinesterase inhibitor. The neuropathological hallmarks of AD are amyloid-rich senile plaques, neurofibrillary tangles, and neuronal degeneration. portfolio currently drugs includes acetylcholinesterase inhibitors (AChEIs) N-methyl-d-aspartate (NMDA) receptor antagonist. Squaric acid is versatile structural scaffold capable easily transformed into amide-bearing compounds that feature both hydrogen...
Interindividual variability in drug response constitutes a major concern pharmacotherapy. While polymorphisms genes involved disposition have been extensively studied, target remains underappreciated. By mapping the genomic of all human onto high-resolution crystal structures complexes, we identified 1094 variants localized within 6 Å drug-binding pockets and directly affecting their geometry, topology, or physicochemical properties. We experimentally show that binding site affect...
Tacrine was withdrawn from clinical use as a drug against Alzheimer's disease in 2013, mainly due to drug-induced liver injury. The culprit of tacrine-associated hepatotoxicity is believed be the 7-OH-tacrine metabolite, possible precursor quinone methide (Qmeth), which binds intracellular -SH proteins. In our study, several different animal and human models (liver microsomes, primary hepatocytes, slices) were used investigate biotransformation tacrine its 7-substituted analogues...
Acetylcholinesterase cysteine-targeted insecticides against malaria vector Anopheles gambia and other mosquitos have already been introduced. We applied the olefin metathesis for preparation of in high yields. The prepared compounds with either a succinimide or maleimide moiety were evaluated on gambiae human acetylcholinesterase relatively irreversible inhibition both enzymes but poor selectivity. concept cysteine binding was not proved by several methods, stability observed chosen most...
Alzheimer’s disease (AD) is a complex with an unknown etiology. Available treatments, limited to cholinesterase inhibitors and N-methyl-d-aspartate receptor (NMDAR) antagonists, provide symptomatic relief only. As single-target therapies have not proven effective, rational specific-targeted combination into single molecule represents more promising approach for treating AD, expected yield greater benefits in alleviating symptoms slowing progression. In the present study, we designed,...
Tacrine (THA), a long withdrawn drug, is still popular scaffold used in medicinal chemistry, mainly for its good reactivity and multi-targeted effect. However, THA-associated hepatotoxicity an issue must be considered drug discovery based on the THA scaffold. Following our previously identified hit compound 7-phenoxytacrine (7-PhO-THA), we systematically explored chemical space with 30 novel derivatives, focus low hepatotoxicity, anticholinesterase action, antagonism at GluN1/GluN2B subtype...
Nervově paralytické látky (NPL) patří mezi organofosforové inhibitory (OFI) acetylcholinesterasy (AChE). Přestože je používání vysoce toxických OFI jako chemických bojových látek zakázáno, byly tyto v minulosti několikrát zneužity. Z těchto důvodů vývoj nových profylakticky účinných sloučenin a terapie intoxikací stále aktuální. Podáním běžných antidot (např. oximových reaktivátorů) se nejen zvyšuje odolnost organismu proti účinkům NPL při očekávané intoxikaci, např. práci zamořeném...