192 research outputs found
Dynamical model of the E. coli MurD enzyme and in silico design of novel inhibitors
No full textV zadnjih letih opažamo precejšen porast identificiranih patoloških bakterijskih sevov, ki so odporni na večino znanih protibakterijskih zdravilnih učinkovin. Tako zaskrbljujoče stanje kaže na nujnost pospešenega iskanja novih protibakterijskih učinkovin v vlogi učinkovitega orožja za boj proti patološkim prokariontskim organizmom. Med mnogimi že znanimi in na novo identificiranimi potencialnimi tarčami so encimi, ki sodelujejo v biosintezi bakterijskega peptidoglikana, že dlje časa zanimive tarče zaradi možnosti doseganja selektivne toksičnosti. Sinteza peptidnega dela monomerne enote peptidoglikana poteka intracelularno preko sukcesivnega dodajanja aminokislin na začetni UDP-prekurzor (UDP-MurNAc), ki ga katalizirajo visoko specifični encimi, imenovani Mur sintetaze (MurC, MurD, MurE in MurF). Med njimi encim MurD (UDP-N-acetilmuramil-L-Ala:D-Glu ligaza) katalizira reakcijo tvorbe peptidne vezi med D-glutamatom in uridindifosfatnim (UDP) prekurzorjem UDP-MurNAc-L-Ala (UMA), ki je sočasno sklopljena s hidrolizo energijske molekule ATP od ADP in prostega fosfata Pi.V doktorskem delu smo z metodami molekulskega modeliranja postavili kompleksen dinamični model encima MurD iz bakterijske vrste E. coli, ki povezuje do sedaj znana
eksperimentalna spoznanja o tej protibakterijski tarči, in z in silico metodami strukturno podprtega načrtovanja zdravilnih učinkovin identificirali nove inhibitorje Mur ligaz. Z uporabo tarčne molekulske dinamike (TMD) smo, izhajajoč iz objavljenih eksperimentalno določenih odprtih in zaprtih struktur encima, postavili dinamične modele vezave obeh substratov (ATP in UMA) v njuni aktivni mesti in analizirali zapiranje C-terminalne domene MurD. Poleg reproduciranega zaporedja vezave substratov, so TMD simulacije pokazale, da v obratu C-terminalne domene sodeluje več aminokislin. Med njimi še posebej izstopata aminokislinska preostanka Pro300 in Arg302. Simulacije »off-path« tehnike (OPS), ki so razširitev že uveljavljene metode replik (RPATh), smo uporabili za določitev energetike zapiranja C-terminalne domene, ki smo jo dobili s pomočjo TMD simulacij. Rezultati so pokazali, da je prehod iz odprte MurD strukture 1EEH v zaprto 2UAG energijsko bistveno zahtevnejši od prehoda, izhajajočega iz odprte 1E0D strukture. Gibanja Cterminalne domene, ki so omejena na ravnino centralne in N-terminalne domene, so energijsko bistveno manj zahtevna kot gibanje iz te ravnine. S hibridnimi kvantnomehansko/molekulskomehanskimi (QM/MM) metodami smo študirali tri možne mehanizme nastanka tetraedričnega intermediata encima MurD, ki pogosto predstavlja začetno strukturo pri razvoju MurD inhibitorjev. Reakcijske poti med optimiziranimi začetnimi strukturami, konstruiranimi na osnovi dostopnih eksperimentalnih podatkov in tetraedričnimi intermediati smo določili s QM/MM različico metode replik (RPATh). Dobljeni molekularni modeli encimske reakcije so v skladu z ekspermentalnim reakcijskim vrstnim redom in kažejo, da v reakciji najprej reagira substrat UMA z ATP molekulo v acilfosfatni intermediat in da se D-Glutaminska kislina najverjetneje pred reakcijo z acil-fosfatnim intermediatom deprotonira. Simulacije proste energije vezave, izvedene z metodo linearne interakcijske energije (LIE) v seriji Nsulfonilnih derivatov glutaminske kisiline, so reproducirale eksperimentalno določene vrednosti DGvezave. Rezultati simulacij kažejo, da najpomembnejšo vlogo pri vezavi teh inhibitorjev igrajo van der Waalsove interakcije. Energijska analiza prispevkov posameznih delov inhibitorjev (glutaminska kislina, naftalenski del, sulfonamidni del in lipofilni rep) k celotni vezavi je kvantificirala pomen posameznih strukturnih fragmentov, ki sestavljajo ta razred spojin. Izhajajoč iz dostopnih strukturnih podatkov za encima MurD in MurE (oba iz E. coli) smo razvili protokol virtualnega rešetanja (VS), ki je s kombinacijo trodimenzionalnih farmakoforov in
molekulskega sidranja služil preiskovanju velikih knjižnic virtualnih molekul. Identificirali smo nov razred dualnih inhibitorjev encimov MurD in MurE, ki kot možen nadomestek za glutaminsko kislino, vsebujejo benzen 1,3- dikarboksilatni fragment.The increasing incidence of bacterial resistance to most available antibiotics has made the discovery of novel efficacious antibacterial agents urgent. In this process, previously unexploited targets are being considered. As an essential bacterial component unique to prokaryotic cells, peptidoglycan is traditionally an optimal target with respect to selective toxicity. Four ADP-forming bacterial ligases – MurC, MurD, MurE, and MurF – are involved in the intracellular phase of peptidoglycan assembly, catalyzing the synthesis of a peptide moiety by consecutive addition of the amino acids to the starting UDP-precursor (UDP-MurNAc). Among them the MurD (UDP-N-acetylmuramoyl-L-alanine:Dglutamate ligase) catalyses a highly specific incorporation of the D-glutamate into the cytoplasmic intermediate UDP-N-acetyl-muramoyl-L-alanine (UMA) utilizing ATP hydrolysis to ADP and Pi. In this work by using various molecular modeling methodologies a complex dynamical model for the MurD enzyme from the E. coli bacterial species was derived at the atomic level, taking into consideration all the available experimental observations. Furthermore, in silico structure-based drug design approach was utilized leading to the identification of novel inhibitors of Mur ligase family.
Targeted nanosecond molecular dynamics (TMD) simulations were performed in order to examine the substrate (ATP and UMA) binding process and gain insight into structural changes that occur during the conformational closure of the MurD C-terminal domain into the active conformation. The experimentally determined binding order of the substrates was reproduced by TMD simulations. The key interactions essential for the conformational transitions (amino acid residues: Pro300 in Ar302) and substrate binding were identified. Off-path simulation (OPS) technique, an extension of the established Replica path method (RPATh), was initiated to evaluate the energy pathway of the two TMD-generated C-terminal domain closing pathways. The study established much higher energy demands if the C-terminal domain closing process commenced from the open structure in which this domain is located out-of plane with respect to the N-terminal and central domains (open structure 1EEH) in comparison to the open structure in which the conformational movement is confined to this plane (open structure 1E0D). A hybrid quantum mechanical/molecular mechanical (QM/MM) molecular modeling approach was utilized, to evaluate three possible reaction pathways leading to the tetrahedral intermediate formation – a frequent drug design starting point. Geometries of the starting structures based on crystallographic experimental data and tetrahedral intermediates were carefully examined together with a role of crucial amino acids and water molecules. The QM/MM replica path method (RPATh) was used to generate the reaction pathways between the starting structures and the corresponding tetrahedral reaction intermediates, producing reaction pathways which were in agreement with in a sequential kinetic mechanism. The D-Glu moiety most likely enters the enzyme reaction in its deprotonated form. Binding free energies were calculated for a series of MurD N-sulphonyl-glutamic acid inhibitors using the Linear Interaction Energy (LIE) method. Analysis of interaction energy revealed non-polar van der Waals interactions as the main driving force for the binding of these inhibitors, and excellent agreement with the experimental free energies was obtained. Analysis of fragment contribution to binding free energies for selected inhibitor moieties (glutamic acid, sulphone amide group, naphthalene moiety and lipophilic tail) in this structural class substantiated the insight into the source of inhibitory activity. Based on the available structural data for the MurD and MurE enzymes (both from E. coli) a virtual screening campaign was performed, combining three-dimensional structure-based pharmacophores and molecular docking calculations, resulting in the identification of a novel class of glutamic acid surrogates - benzene 1,3-dicarboxylic acid derivatives possessing dual MurD and MurE inhibitory activity
Cluster-based molecular docking study for in silico identification of novel 6-fluoroquinolones as potential inhibitors against Mycobacterium tuberculosis (Cover Page)
No full text<p>The rapid development of drug resistance in microbes, the toxicity, and side effects of existing anti-infectious drugs are factors stimulating the effort directed toward a new generation of antibiotics. On page 790, Nikola Minovski, Andrej Perdih, Marjana Novic, and Tom Solmajer demonstrate how carefully validated in silico models using the recently determined structures of M. tuberculosis– DNA gyrase apoprotein and topoisomerase II-DNA-6-fluoroquinolones complexes are proficiently used for defining the drugs' binding pockets and the subsequent design of a series of novel inhibitors of DNA gyrase from the class of substituted 6-fluoroquinolones (shown on the cover).</p
Prediction of endocrine activity of colours permitted to use in comsetic products with in silico method
No full textSplošni razlagalni slovarji slovanskih jezikov
No full textThe monograph ('General Monolingual Dictionaries of the Slavic Languages') provides an overview of the more prominent dictionary typologies, and an overview of general monolingual Slavic language dictionaries created from 1945 untill the present. The analysis presents how dictionary elements of selected dictionaries are treated at the macrostructural and microstructural level. For selected elements (homonymy and homography, multi-word headwords, sub-entries, grammatical information, referential definition type, multi-word lexical units and etymological information), suggestions for further lexicographical practice are given. The standpoint of these suggestions is that a dictionary serves as a representation of a lexicon and as a practical tool, which should effectively and transparently deliver reliable and relevant linguistic data and to a lesser extent non-linguistic data. The suggestions also take into account the completed transition from the initial print dictionary to the initial electronic dictionary, which to a certain extent requires reallocation of the data and to a lesser extent reorganization of data hierarchy.Monografija prinaša pregled vidnejših slovarskih tipologij, pregled splošnih enojezičnih slovanskih slovarjev, nastalih od 1945 do danes. Analiza prikazuje obravnavo slovarskih prvin na makrostrukturni in mikrostrukturni ravni. Za izbrane elemente (homonimija in homografija, večbesedne iztočnice, podgesla, slovnični podatki, sklicevalni tip razlage, večbesedne leksikalne enote in etimološki podatki) so podani predlogi za nadaljnjo slovaropisno prakso. Izhodišče teh predlogov je slovar kot jezikovni opis besedja in kot praktični pripomoček, ki naj kar se da učinkovito in pregledno prinaša zanesljive in relevantne jezikovne in, v manjši meri, tudi nejezikovne podatke, pri predlogih pa je upoštevan tudi zaključen prehod od izhodiščno knjižne podobe slovarja k izhodiščno digitalni podobi slovarja, kar do določene mere zahteva prerazporeditev slovarskih podatkov, v manjši meri pa tudi preureditev njihove hierarhije
Dynamical model of a type II DNA topoisomerase and in silico design of novel catalytic inhibitors as potential chemotherapeutics
No full textDNA topoizomeraze tipa II so biološki molekulski motorji, ki katalizirajo topološke spremembe v molekuli DNA in so pomembne tarče protirakavih zdravil. S pomočjo molekulskih simulacij in eksperimentalnih podatkov smo razvili dinamičen model različnih konfiguracij topoizomeraze IIA v njenem katalitičnem ciklu. Simulacije so pokazale, da sta rotacijsko gibanje dimera in drsno gibanje znotraj DNA-vrat inherentni dinamični lastnosti encima. Ugotovili smo tudi, da ATP ključno prispeva k stabilizaciji T-segmenta, saj hidroliza ATP povečuje konformacijsko aktivnost N-vrat.
Načrtovali smo katalitične zaviralce človeške topoizomeraze II?, ki ciljajo na vezavno mesto za ATP, da bi obšli omejitve obstoječih topoizomeraznih strupov, ki se uporabljajo v kemoterapiji. Z uporabo molekulskih simulacij in umetne inteligence smo optimizirali zaviralce iz skupine 4,6-substituiranih-1,3,5-triazin-2(1H)-onov, pri čemer so uvedeni biciklični substituenti na mestu 6 ohranili zaviralno aktivnost in nekoliko izboljšali fizikalno-kemijske lastnosti spojin. Razvili smo tudi novo metodo načrtovanja učinkovin s pomočjo dinamičnih farmakofornih modelov. Za validacijo metode smo uporabili vezavno mesto za ATP človeške DNA topoizomeraze II? ter odkrili nove katalitične zaviralce naravnega izvora. Z uporabo tako razvitega farmakofornega modela smo odkrili substituirane 3-(imidazol-2-il) morfoline, ki selektivno zavirajo topoizomerazo II? in se vežejo na ATPazno domeno. Te spojine so tudi citotoksične preko mehanizma, ki je drugačen kot pri topoizomeraznih strupih.Type II DNA topoisomerases are biological molecular motors that catalyze topological changes in DNA molecules and are considered important targets for anticancer drugs. Using molecular simulations and experimental data, we developed a dynamic model of various configurations of topoisomerase IIA in its catalytic cycle. The simulations revealed that both the rotational movement of the dimer and the sliding motion within the DNA gates are inherent dynamic properties of the enzyme. Furthermore, ATP could play a crucial role in the stabilization of the T-segment, as ATP hydrolysis increased the conformational activity of the N-gate.
To overcome the limitations of current topoisomerase poisons used in chemotherapy catalytic inhibitors of human topoisomerase IIα that target the ATP binding site were developed. By utilizing molecular simulations and artificial intelligence, we optimized inhibitors from the group of 4,6-substituted-1,3,5-triazine-2(1H)-ones, where the introduced bicyclic substituents at position 6 maintained inhibitory activity and somewhat improved the physicochemical properties of the compounds. In addition, a novel approach for designing compounds was developed using dynamic pharmacophore models. To validate this method, the ATP binding site of human DNA topoisomerase IIα was examined, and new catalytic inhibitors of natural origin were identified. The derived pharmacophore model was then used to identify a class of substituted 3-(imidazol-2-yl) morpholines which selectively inhibit topoisomerase IIα and bind to its ATPase domain. These compounds also exhibit cytotoxic properties through a mechanism that is different from that of topoisomerase poisons
Dictionary of New Slovenian Words - SNB (ELEXIS)
No full textSlovar novejšega besedja slovenskega jezika.
Dictionary of New Slovenian Words represents a basic new lexical supplement to the Slovar slovenskega knjižnega jezika (Dictionary of the Slovenian Standard Language). It contains 6399 new words and phrases that appeared in Slovenian or gained ground after 1991 as well as new meanings of previously standardised lexis. Two important new features of the dictionary are a corpus-driven analysis of new words that are in actual language use and etymological explanations of the included words.
See also: http://hdl.handle.net/11356/1091
This dictionary was published as a printed book:
Bizjak Končar, Aleksandra, Snoj, Marko, Gložančev, Alenka, Kern, Boris, Kostanjevec, Polona, Krvina, Domen, Ledinek, Nina, Michelizza, Mija, Perdih, Andrej, Petric, Špela, Šircelj-Žnidaršič, Ivanka, Žele, Andreja, Mirtič, Tanja, Gliha Komac, Nataša, Klemenčič, Simona. Slovar novejšega besedja slovenskega jezika. Ljubljana : Založba ZRC, ZRC SAZU, 2012
Application of molecular modeling methods in design and optimization of inhibitors of the human DNA topoisomerase II[alpha]
No full textDictionary of New Slovenian Words
No full textSlovar novejšega besedja slovenskega jezika (Dictionary of New Slovenian Words) represents a basic new lexical supplement to the Slovar slovenskega knjižnega jezika (Dictionary of the Slovenian Standard Language). It contains 6399 new words and phrases that appeared in Slovenian or gained ground after 1991 as well as new meanings of previously standardised lexis. Two important new features of the dictionary are a corpus-driven analysis of new words that are in actual language use and etymological explanations of the included words.
This dictionary was published as a printed book:
Bizjak Končar, Aleksandra, Snoj, Marko, Gložančev, Alenka, Kern, Boris, Kostanjevec, Polona, Krvina, Domen, Ledinek, Nina, Michelizza, Mija, Perdih, Andrej, Petric, Špela, Šircelj-Žnidaršič, Ivanka, Žele, Andreja, Mirtič, Tanja, Gliha Komac, Nataša, Klemenčič, Simona. Slovar novejšega besedja slovenskega jezika. Ljubljana : Založba ZRC, ZRC SAZU, 2012. ISBN 978-961-254-413-3
Portal Fran: od začetkov do danes
No full textInternetski Portal Fran: Rječnici Instituta za slovenski jezik Frana Ramovša ZRC SAZU osnovan je u listopadu 2014. Zauzeo je mjesto glavnog rječničkog portala za slovenski jezik. U članku se opisuje daljnji razvoj portala od godine 2015. do rujna 2019., kad je fokus bio na integriranju novih sadržaja i poboljšanju funkcionalnosti, prikaza i korisničkog iskustva te izgradnji aplikacija za operativne sustave Android i iOS. Kontinuiranim razvojem portala razvijena su najinovativnija rješenja za one rječnike koji se koriste mogućnostima digitalnog objavljivanja rječnika, odnosno mrežnim grafičkim prikazom međuleksemskih odnosa, slikovnim i zvučnim materijalima i mapama za identificiranje mjesta u dijalektnim rječnicima. Također se pokazuju načini integriranja dodatnih sadržaja koji portal sadržajno proširuju s rječničkog portala na središnji portal o slovenskom jeziku.The Fran: Dictionaries of the Fran Ramovš Institute of the Slovenian Language ZRC SAZU web portal was launched in october 2014. The content of the portal describes the Slovenian language in its contemporary literary, dialectal, and historical forms. At the time of publication, it consisted of 21 dictionaries and linguistic atlases, two language counseling services, and hyperlinks to corpora and other language resources.
The article focuses on the later development of the portal, wherein the main goals were the inclusion of new content and improvements to its functionality, visualization, user experience, and development of applications for Android and ioS operating systems. From 2015 to September 2019, the number of dictionaries published on the portal rose to 36. Several previously unpublished dictionaries, other language resources, and software have been added, including the ZRCola special characters input system, and the Slovenian grammars and orthographic dictionaries sub-portal consisting of publications from 1584 until the present day. Continued development of the portal has brought various innovative solutions for the presentation of dictionaries in the digital form, e.g. graphic representation of interlexemic relations, image and sound material, and the use of maps for easier geographical presentation of the areas dialectal dictionaries cover. The article also presents approaches to the integration of additional content that extends the role of the portal to the central web portal on the Slovenian language.Internetni Portal Fran: Slovarji Inštituta za slovenski jezik Frana Ramovša ZRC SAZU je bil vzpostavljen oktobra 2014 in je prevzel mesto glavnega slovarskega portala za slovenski jezik. Prispevek opisuje nadaljnji razvoj portala od leta 2015 do septembra leta 2019, ko je bilo v ospredju vključevanje novih vsebin ter izboljšanje funkcionalnosti, prikaza in uporabniške izkušnje ter izdelava aplikacij za operacijske sisteme Android in iOS. Ob kontinuiranem postopnem razvoju portala je bilo največ inovativnih rešitev pripravljenih pri tistih slovarjih, ki izkoriščajo možnosti digitalne objave slovarjev, in sicer mrežni grafični prikaz medleksemskih razmerij, slikovni in zvočni material ter uporaba zemljevida za identifikacijo lokacije narečnih slovarjev. Prikazani so tudi načini vključevanja dodatnih vsebin, ki portal vsebinsko širijo iz slovarskega portala v osrednji portal o slovenskem jeziku
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