in silico modelling Dotaz Zobrazit nápovědu
243 s. : il. ; 21 cm
- MeSH
- analýza nákladů a výnosů MeSH
- efektivita organizační MeSH
- kvalita zdravotní péče MeSH
- operační výzkum MeSH
- počítačová simulace MeSH
- programy národního zdraví MeSH
- stárnutí MeSH
- výzkum MeSH
- zdravotnické plánování MeSH
- Publikační typ
- kongresy MeSH
- sborníky MeSH
- Konspekt
- Veřejné zdraví a hygiena
- NLK Obory
- management, organizace a řízení zdravotnictví
253 stran : ilustrace ; 21 cm
- MeSH
- biomedicínské technologie MeSH
- lékařská informatika MeSH
- počítačová simulace MeSH
- Publikační typ
- kongresy MeSH
- sborníky MeSH
- Konspekt
- Lékařské vědy. Lékařství
- NLK Obory
- lékařská informatika
- MeSH
- biomechanika MeSH
- externí fixátory trendy využití MeSH
- otevřené fraktury terapie MeSH
- počítačová simulace využití MeSH
- Publikační typ
- přehledy MeSH
A review on applicability of in silico methods for toxicity testing by calculation for regulatory purposes, their survey and background of QSAR (Quantitative Structure-Activity Relationships) analysis are presented.
Human cytosolic prolyl-tRNA synthetase (HcProRS) catalyses the formation of the prolyl-tRNAPro, playing an important role in protein synthesis. Inhibition of HcProRS activity has been shown to have potential benefits in the treatment of fibrosis, autoimmune diseases and cancer. Recently, potent pyrazinamide-based inhibitors were identified by a high-throughput screening (HTS) method, but no further elaboration was reported. The pyrazinamide core is a bioactive fragment found in numerous clinically validated drugs and has been subjected to various modifications. Therefore, we applied a virtual screening protocol to our in-house library of pyrazinamide-containing small molecules, searching for potential novel HcProRS inhibitors. We identified a series of 3-benzylaminopyrazine-2-carboxamide derivatives as positive hits. Five of them were confirmed by a thermal shift assay (TSA) with the best compounds 3b and 3c showing EC50 values of 3.77 and 7.34 µM, respectively, in the presence of 1 mM of proline (Pro) and 3.45 µM enzyme concentration. Co-crystal structures of HcProRS in complex with these compounds and Pro confirmed the initial docking studies and show how the Pro facilitates binding of the ligands that compete with ATP substrate. Modelling 3b into other human class II aminoacyl-tRNA synthetases (aaRSs) indicated that the subtle differences in the ATP binding site of these enzymes likely contribute to its potential selective binding of HcProRS. Taken together, this study successfully identified novel HcProRS binders from our anti-tuberculosis in-house compound library, displaying opportunities for repurposing old drug candidates for new applications such as therapeutics in HcProRS-related diseases.
- MeSH
- adenosintrifosfát metabolismus MeSH
- aminoacyl-tRNA-synthetasy antagonisté a inhibitory MeSH
- biotest metody MeSH
- inhibitory enzymů chemie izolace a purifikace farmakologie MeSH
- konformace proteinů MeSH
- krystalografie rentgenová MeSH
- lidé MeSH
- ligandy MeSH
- molekulární modely MeSH
- počítačová simulace * MeSH
- pyrazinamid chemie MeSH
- vazebná místa MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Advances in simulation ; vol. 6
[1st ed.] XVI, 517 s. : obr., schém. tab. ; 23cm
- Konspekt
- Lékařské vědy. Lékařství
- NLK Obory
- lékařská informatika
- fyziologie
Investigating microorganisms in metal-enriched environments holds the potential to revolutionize the sustainable recovery of critical metals such as lanthanides (Ln3+). We observe Hyphomicrobium spp. as part of a Fe2+/Mn2+-oxidizing consortia native to the ferruginous bottom waters of a Ln3+-enriched lake in Czechia. Notably, one species shows similarities to recently discovered bacteria expressing proteins with picomolar Ln3+ affinity. This finding was substantiated by developing an in-silico ionic competition model and recombinant expression of a homolog protein (Hm-LanM) from Hyphomicrobium methylovorum. Biochemical assays validate Hm-LanM preference for lighter Ln3+ ions (from lanthanum to gadolinium). This is comparable to established prototypes. Bioinformatics analyses further uncover additional H. methylovorum metabolic biomolecules in genomic proximity to Hm-LanM analogously dependent on Ln3+, including an outer membrane receptor that binds Ln3+-chelating siderophores. These combined observations underscore the remarkable strategy of Hyphomicrobium spp. for thriving in relatively Ln3+ enriched zones of metal-polluted environments.
