A5034494140- Cholinesterase and Neurodegenerative Diseases
- Computational Drug Discovery Methods
- Enzyme Catalysis and Immobilization
- Enzyme Structure and Function
- Protein Structure and Dynamics
- Chemical synthesis and alkaloids
- Enzyme function and inhibition
- Chemical Reaction Mechanisms
- Photosynthetic Processes and Mechanisms
- Alzheimer's disease research and treatments
- Pesticide Exposure and Toxicity
- Microbial Metabolic Engineering and Bioproduction
- Cultural Heritage Materials Analysis
- Vitamin C and Antioxidants Research
- Plant Stress Responses and Tolerance
- Tuberculosis Research and Epidemiology
- Carbohydrate Chemistry and Synthesis
- Dysphagia Assessment and Management
- Environmental Toxicology and Ecotoxicology
- Protein Degradation and Inhibitors
- bioluminescence and chemiluminescence research
- Metal-Catalyzed Oxygenation Mechanisms
- Genomics and Phylogenetic Studies
- Microbial Metabolism and Applications
- Inorganic and Organometallic Chemistry
Institute of Crystallography
2010-2024
National Research Council
2024
National Research Council
2012-2024
AREA Science Park
2005-2023
University of Trieste
2007
Scuola Internazionale Superiore di Studi Avanzati
2005
University of Bologna
2001
Ospedali Riuniti Umberto I
1991
We report the identification of multitarget anti-Alzheimer compounds designed by combining a naphthoquinone function and tacrine fragment. In vitro, 15 displayed excellent acetylcholinesterase (AChE) inhibitory potencies interesting capabilities to block amyloid-β (Aβ) aggregation. The X-ray analysis one those in complex with AChE allowed rationalizing outstanding activity data (IC50 = 0.72 nM). Two showed negligible toxicity immortalized mouse cortical neurons Neuro2A primary rat cerebellar...
Twenty-six new tacrine–benzofuran hybrids were designed, synthesized, and evaluated in vitro on key molecular targets for Alzheimer's disease. Most exhibited good inhibitory activities cholinesterases β-amyloid self-aggregation. Selected compounds displayed significant inhibition of human β-secretase-1 (hBACE-1). Among the 26 hybrids, 2e showed most interesting profile as a subnanomolar selective inhibitor acetylcholinesterase (hAChE) (IC50 = 0.86 nM) both aggregation (hAChE- self-induced,...
Abstract Chemical warfare nerve agents and pesticides, known as organophosphorus compounds inactivate cholinesterases (ChEs) by phosphorylating the serine hydroxyl group located at active site of ChEs. Over course time, phosphorylation is followed loss an organophosphate‐leaving bond with ChEs becomes irreversible, a process aging. Differently, structurally related irreversible catalytic poisons bearing sulfur instead phosphorus convert in its aged form only covalently binding to key serine....
Acetylcholinesterase inhibitors were introduced for the symptomatic treatment of Alzheimer's disease (AD). Among currently approved inhibitors, donepezil (DNP) is one most preferred choices in AD therapy. The X-ray crystal structures Torpedo californica AChE complex with two novel rigid DNP-like analogs, compounds 1 and 2, have been determined. Kinetic studies indicated that 2 show a mixed-type inhibition against TcAChE, Ki values 11.12 ± 2.88 29.86 1.12 nM, respectively. DNP rigidification...
Pyrazinamidase of Mycobacterium tuberculosis catalyzes the conversion pyrazinamide to active molecule pyrazinoic acid. Reduction pyrazinamidase activity results in a level resistance. Previous studies have suggested that has metal-binding site and divalent metal cofactor is required for activity. To determine effect metals on pyrazinamidase, recombinant wild-type corresponding H37Rv pyrazinamide-susceptible reference strain was expressed Escherichia coli with without carboxy terminal....
The Michaelis-Menten model of enzyme kinetic assumes the free ligand approximation, steady-state approximation and rapid equilibrium approximation. Analytical methods to slow-binding inhibitors by analysis initial velocities have been developed but, due their inherent complexity, they are seldom employed. In order circumvent complications that arise from violation assumption, inhibition is commonly evaluated pre-incubating so that, even for slow inhibitors, binding established before...
Pax-8 is a member of the Pax family transcription factors and essential in development thyroid follicular cells. has two DNA-binding domains: paired domain homeo domain. In this study, preliminary X-ray diffraction analysis mammalian complex with C-site thyroglobulin promoter was achieved. The crystallized by hanging-drop vapor-diffusion method both blunt-ended 26 bp DNA fragment sticky-ended 24 additional overhanging bases. Crystallization experiments make clear that growth transparent...
Activation-by-inhibition is a biochemical paradox seldom observed in exosite enzymes, wherein active site-bound inhibitors unexpectedly lead to enzyme activation. This intriguing phenomenon occurs at low, undersaturating substrate concentrations, posing significant challenge drug discovery, especially when targeting enzymes such as protein kinases, proteases, and other posttranslational modification enzymes. These often rely on accessory recognition sites known exosites, which contribute...