A5036896327- Click Chemistry and Applications
- Chemical Synthesis and Analysis
- Peptidase Inhibition and Analysis
- Protein Degradation and Inhibitors
- Computational Drug Discovery Methods
- Ubiquitin and proteasome pathways
- PARP inhibition in cancer therapy
- Biotin and Related Studies
- Phytochemicals and Medicinal Plants
- Synthesis and Biological Evaluation
- Monoclonal and Polyclonal Antibodies Research
- Pneumocystis jirovecii pneumonia detection and treatment
- Pharmacological Effects and Assays
- Antimicrobial Resistance in Staphylococcus
- Organophosphorus compounds synthesis
- Quinazolinone synthesis and applications
- Cancer Mechanisms and Therapy
- Cellular transport and secretion
- Process Optimization and Integration
- Calcium signaling and nucleotide metabolism
- Histone Deacetylase Inhibitors Research
- Carbohydrate Chemistry and Synthesis
- Asymmetric Hydrogenation and Catalysis
- Biochemical and Molecular Research
- SARS-CoV-2 and COVID-19 Research
HUN-REN Research Centre for Natural Sciences
2018-2025
Eötvös Loránd University
2024
Budapest University of Technology and Economics
2015-2023
Medicina
2020
Photoaffinity labeling is a widely used methodology for interrogating small molecule‐protein interactions. However, these applications are limited by the few photo‐cross‐linkers that typically modify affinity and binding mode of original ligand. Here, we report development new target agnostic photoaffinity warheads, sulfohydrazones form reactive carbene upon UV irradiation. Careful optimization reaction conditions allowed us to effectively label five different amino acid residues in...
Photoaffinity labeling is a widely used methodology for interrogating small molecule‐protein interactions. However, these applications are limited by the few photo‐cross‐linkers that typically modify affinity and binding mode of original ligand. Here, we report development new target agnostic photoaffinity warheads, sulfohydrazones form reactive carbene upon UV irradiation. Careful optimization reaction conditions allowed us to effectively label five different amino acid residues in...
Labeling proteins with covalent ligands is finding increasing use in proteomics applications, including identifying nucleophilic residues amenable for labeling and the development of targeted inhibitors (TCIs). efficiency measured by occupancy target or biochemical activity. Here, we investigate how these observed quantities relate to intrinsic parameters complex formation, namely, noncovalent affinity reactivity, experimental conditions, incubation time ligand concentration. It shown that...
Targeted covalent inhibitors represent a viable strategy to block protein kinases involved in different disease pathologies. Although number of computational protocols have been published for identifying druggable cysteines, experimental approaches are limited mapping the reactivity and accessibility these residues. Here, we present ligand based approach using toolbox fragment-sized molecules with identical scaffold but equipped diverse warheads. Our library represents unique opportunity...
Targeted covalent inhibitors represent an increasingly popular approach to modulate challenging drug targets. Since and non-covalent interactions are both contributing the affinity of these compounds, evaluation their reactivity is a key-step find feasible warheads. There well-established HPLC- NMR-based kinetic assays tackle this task, however, they use variety cysteine-surrogates including cysteamine, cysteine or acetyl-cysteine GSH. The diverse nature thiol sources often makes results...
Here we present WIDOCK, a virtual screening protocol that supports the selection of diverse electrophiles as covalent inhibitors by incorporating ligand reactivity towards cysteine residues into AutoDock4. WIDOCK applies reactive docking method (Backus et al. in Nature 534:570-574, 2016) and extends it tool introducing facile experimental or computational parametrization focused evaluation scheme together with retrospective prospective validation against various therapeutically relevant...
Screening of ultra-low-molecular weight ligands (MiniFrags) successfully identified viable chemical starting points for a variety drug targets. Here we report the electrophilic analogues MiniFrags that allow mapping potential binding sites covalent inhibitors by biochemical screening and mass spectrometry. Small heterocycles their N-quaternized were first characterized in glutathione assay to analyze reactivity. Next, library was used systematic available human histone deacetylase 8 (HDAC8)....
To date, there are limited options for severe Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 virus. As ADP-ribosylation events involved in regulating the life cycle of coronaviruses and inflammatory reactions host; we have, here, assessed repurposing registered PARP inhibitors treatment COVID-19.
Protein labelling has a wide variety of applications in medicinal chemistry and chemical biology. In addition to covalent inhibition, specific biomolecules with fluorescent dyes is important both target discovery, validation diagnostics. Our research was conducted through the fragment-based development new benzyl-isothiocyanate-activated dye based on fluorescein scaffold. This molecule evaluated against isothiocyanate, prevalent agent. The reactivity selectivity phenyl- benzyl isothiocyanate...
Drug discovery programs against the antibacterial target UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) have already resulted in covalent inhibitors having small three- and five-membered heterocyclic rings. In current study, reactivity of four-membered rings was carefully modulated to obtain a novel family MurA inhibitors. Screening library cyclobutenone derivatives led identification bromo-cyclobutenaminones as new electrophilic warheads. The cysteine specificity been determined...
Intrinsically disordered proteins (IDPs) play important roles in disease pathologies; however, their lack of defined stable 3D structures make traditional drug design strategies typically less effective against these targets. Based on promising results targeted covalent inhibitors (TCIs) challenging targets, we have developed a strategy targeting IDPs. As model system chose tau, an endogenous IDP the central nervous that is associated with severe neurodegenerative diseases via its...
MurA (UDP-N-acetylglucosamine enolpyruvyl transferase) catalyzes the first committed step in cytoplasmic part of peptidoglycan biosynthesis and is a validated target enzyme for antibacterial drug discovery; inhibitor fosfomycin has been used clinically decades. Like fosfomycin, most inhibitors are small heterocyclic compounds that inhibit by forming covalent bond with active site cysteine. The reactive chloroacetamide group was selected from series suitable electrophilic thiol-reactive...
Targeted covalent inhibition and the use of irreversible chemical probes are important strategies in biology drug discovery. To date, availability reactivity cysteine residues amenable for targeting have been evaluated by proteomic computational tools. Herein, we present a toolbox fragments containing 3,5-bis(trifluoromethyl)phenyl core that was equipped with chemically diverse electrophilic warheads showing range reactivities. We characterized library members their reactivity, aqueous...
SuFEx chemistry is based on the unique reactivity of sulfonyl fluoride group with a range nucleophiles. Accordingly, fluorides label multiple nucleophilic amino acid residues, making these reagents popular in both chemical biology and medicinal applications. The nominates this warhead chemotype as candidate for an external, activation-free general labelling tag. Here, we report synthesis characterization small library that yielded 3-carboxybenzenesulfonyl tagging tractable targets at...
Covalent drugs might bear electrophiles to chemically modify their targets and have the potential target previously undruggable proteins with high potency. binding of drug-size molecules includes a noncovalent recognition provided by secondary interactions chemical reaction leading covalent complex formation. Optimization mechanism action should involve both types interactions. Noncovalent steps can be characterized an equilibrium dissociation constant (KI) rate (kinact), respectively, they...
Abstract Patients infected with SARS-CoV-2 risk co-infection Gram-positive bacteria, which severely affects their prognosis. Antimicrobial drugs dual antiviral and antibacterial activity would be very useful in this setting. Although glycopeptide antibiotics are well-known as strong drugs, some of them also active against RNA viruses like SARS-CoV-2. It has been shown that the efficacy can enhanced by synthetic modifications. We here report synthesis biological evaluation seven derivatives...
Heterocyclic electrophiles as small covalent fragments showed promising inhibitory activity on the antibacterial target MurA (UDP-N-acetylglucosamine 1-carboxyvinyltransferase, EC:2.5.1.7). Here, we report second generation of heterocyclic electrophiles: quaternized analogue fragment library with improved reactivity and potency. Quantum chemical reaction barrier calculations, GSH (L-glutathione) assay, thrombin counter screen were also used to demonstrate explain selectivity N-methylated...
Constitutive- and immunoproteasomes are part of the ubiquitin–proteasome system (UPS), which is responsible for protein homeostasis. Selective inhibition immunoproteasome offers opportunities treatment numerous diseases, including inflammation, autoimmune hematologic malignancies. Although several inhibitors have been reported, selective nonpeptidic sparse. Here, we describe two series compounds that target both proteasomes. First, benzoxazole-2-carbonitriles as fragment-sized covalent...
Synthesis and characterization of achiral 1 new chiral macrocycles (R,R)-2, (S,S)-3 (S,S)-4 containing a triphenylphosphanone unit have been accomplished.A method was used for the reduction phosphanones to phosphanes.Using this potential catalyst ligands 15, (R,R)-16, (S,S)-17 (S,S)-18 triphenylphosphane were synthesized characterized.These are promising candidates coordination chemistry studies homogeneous catalytic reactions.
G12C mutant KRas is considered druggable by allele-specific covalent inhibitors due to the nucleophilic character of oncogenic cysteine at position 12. Discovery these requires optimization both and noncovalent interactions. Here, we report fragment screening our electrophilic library diverse non-covalent scaffolds equipped with 40 different functionalities identify fragments as suitable starting points targeting Cys12. Screening against KRasG12C using Ellman's free thiol assay, followed...
This study presents the steady-state simulation and optimization with regard to recovery of spent sulfuric acid. Our purpose was prove utility process in terms designing special materials using energy-efficient methods. Process is used order compare technological variants, analyze problems that occur as well optimize process. In this investigation three concentration processes are compared: azeotropic distillation multiple-effect evaporation both co-current counter-current modes. The main...
Fragment screening is a popular strategy of generating viable chemical starting points especially for challenging targets. Although fragments provide better coverage space and they have typically higher chance binding, their weak affinity necessitates highly sensitive biophysical assays. Here, we introduce concept that combines evolutionary optimized fragment pharmacophores with the use photoaffinity handle enables high hit rates by LC-MS-based detection. The sensitivity our protocol was...