Satisfaction With Service Innovations in Serbia

The aim of this paper is to observe the customers satisfaction with service innovations in Serbia. Dealing with the fact that services are generating approximately 71,6 % of EU nominal GDP, it could be said that services are strongly representing the future of economy1. In this paper will be present service innovations in context of their term, importance, classification and the both manifesting forms of service innovations: classical and contemporary. Also, the paper will point to indicate factors for service innovation’s success. Empirical part of this issue obtained interviewees from the field of commerce, banking and public administration. Finally, the service innovations satisfaction degree is determined by SERVQUAL adaptive model and ANOVA application

3D-QSAR студија аналога аденозин 5'-фосфосулфата (APS) као лиганда за APS редуктазу

Metabolism of sulfur (sulfur assimilation pathway, SAP) is one of the key pathways for the pathogenesis and survival of persistant bacteria, such as Mycobacterium tuberculosis (Mtb), in the latent period. Adenosine 5'-phosphosulfate reductase (APSR) is an important enzyme involved in the SAP, absent from the human body, so it might represent a valid target for development of new antituberculosis drugs. This work aimed to develop 3D-QSAR model based on the crystal structure of APSR from Pseudomonas aeruginosa, which shows high degree of homology with APSR from Mtb, in complex with its substrate, adenosine 5'-phosphosulfate (APS). 3D-QSAR model was built from a set of 16 nucleotide analogues of APS using alignment-independent descriptors derived from molecular interaction fields (MIF). The model improves the understanding of the key characteristics of molecules necessary for the interaction with target, and enables the rational design of novel small molecule inhibitors of Mtb APSR.Метаболизам сумпора (пут асимилације сумпора, SAP) један је од кључних путева за патогенезу и преживљавање Mycobacterium tuberculosis (Mtb) у латентном периоду. Аденозин 5'-фосфосфат редуктаза (APSR) је значајан ензим који је укључен у SAP, не налази се у људском организму и може бити валиднo циљно место за развој нових анти- туберкулотика. Циљ овог рада је развој 3D-QSAR модела који се заснива на кристалној структури APSR из Pseudomonas aeruginosa, који има висок степен хомологије са APSR из Mtb, у комплексу са супстратом, аденозин 5'-фосфoсулфатом (APS). 3D-QSAR модел је постављен коришћењем сета 16 нуклеотидних аналога APS применом дескриптора неза- висних од полазних тачака, изведених из поља молекуларних интеракција (MIF). Модел служи за боље разумевање кључних карактеристика молекула неопходних за интерак- цију са циљним местом, у сврху рационалног дизајнирања малих молекула, инхибитора APSR из Mtb

Elucidacija mehanizma dejstva derivata Δ9‐tetrahidrokanabinola iz Cannabis sativa u potencijalnom lečenju multiple skleroze primenom kompjuterskih metoda

Multiple sclerosis (MS) is a disease in which demyelination, neurodegeneration and gliosis occur in the central nervous system. Some constituents of Canabis sativa (CS) extracts are known to have positive effects on symptoms, reduction of progression and healing of MS, whilst roles of particular constituents in extract are not fully elucidated. Late studies show 565 constituents of CS extracts presented and divided in 11 chemical groups. The aim of this study is the investigation of physico-chemical parameters of Δ9 -tetrahydrocannabinol derivatives for further elucidation of their potential effect in treatment of MS. Structures building and geometry optimization were performed by ChemDraw Ultra 8.0 and Chem3D Pro 8.0, whilst descriptors were calculated using MarvinSketch and Codessa software. All 15 Δ9 -tetrahydrocannabinol derivatives showed lipophilicity in wide range (logP from 4.71 to 12.01), which indicates specific mechanism of resorption and bioavailability, including various roles in potential reparation of myelin sheath. Steric parameters indicate wide range of energies of conformation in specific orientation of ligands and additional factors in potentially synergistic action of derivatives in distribution between agonistic and antagonistic action, as well as signalization and modulation of cannabinoid receptors. The presence of ester group in 8 derivatives of tetrahydrocannabinol implies possible role of acyl residues in reparation of myelin sheath. Results could serve as basis for further elucidation of roles of Δ9 -tetrahydrocannabinol derivatives among synergistic engineering of full extract in potential treatment of MS, which concernes both relieving symptoms and healing MS, for which certain levels of evidence exist on human models.Multipla skleroza (MS) je obolјenje u kome dolazi do demijelinizacije, neurodegradacije i glioze u centralnom nervnom sistemu. Poznato je da ekstrakt Canabis sativa (CS) pozitivno utiče na simptome, smanjenje progresije i lečenje MS, pri čemu efekti pojedinačnih konstituenata u ukupnom dejstvu ekstrakta nisu dovoljno razjašnjeni. U novijim istraživanjima, prikazano je ukupno 565 konstituenata ekstrakta CS, svrstanih u 11 hemijskih grupa. Cilј ovog rada je proučavanje fizičko-hemijskih parametara derivata Δ9 - tetrahidrokanabinola u svrhu daljeg razjašnjavanja njihovog potencijalnog efekta u terapiji MS. Prikazivanje i geometrijska optimizacija struktura izvršeni su upotrebom programa ChemDraw Ultra 8.0 i Chem3D Pro 8.0, dok su molekluski deskriptori izračunati korišćenjem programa MarvinSketch i Codessa. Svih 15 derivata Δ9 -tetrahidrokanabinola je pokazalo lipofilnost u širem opsegu (logP od 4.71 do 12.01), što ukazuje na specifičnosti u mehanizmu resorpcije i bioraspoloživosti, ali i različite uloge u potencijalnom obnavljanju mijelinskog omotača. Sterni parametri ukazuju na širok raspon energija konformacije u specifičnoj orijentaciji liganada, dodatne faktore u potencijalno sinergističkom dejstvu konstituenata u raspodeli između agonističkog i antagonističkog dejstva, kao i u ukupnoj signalizaciji i modulaciji kanabinoidnih receptora. Prisustvo estarske grupe kod 8 derivata tetrahidrokanabinola ukazuje na mogućnost učešća acil ostatka u obnovi mijelinskog omotača. Rezultati mogu da posluže kao osnova za dalja razjašnjavanja uloge derivata Δ9 - tetrahidrokanabinola u okviru sinergističkog delovanja ukupnog ekstrakta u potencijalnoj terapiji MS, koji se ne zasniva samo na olakšanju simptoma, već i lečenju MS, za koje postoje različiti nivoi dokaza na humanim modelima.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Inhibitori P-glikoproteina kao modulatori rezistencije na antikancerogene lekove

Multidrug resistance (MDR) is a significant obstacle to providing effective chemotherapy to many patients suffering from different types of cancer. Although resistance to anticancer drugs may be developed by different mechanisms, one of the underlying mechanisms of classical MDR is cellular overexpression of P-glycoprotein (P-gp) which acts as an efflux pump for different substrates in cells, resulting in decreased concentration of anticancer drugs in cancer cells. Inhibiting P-gp as a method to reverse MDR in cancer patients has been studied extensively. The development of Pgp inhibitors from first to third generation is presented in this work. First-generation inhibitors (eg. cyclosporin A, verapamil) are limited by their toxicity, whereas secondgeneration inhibitors (eg. valspodar, biricodar) showed reduced toxicity but were confounded by unpredictable pharmacokinetic interactions with anticancer drugs as well as interactions with other transporter proteins. Third-generation inhibitors (tariquidar, zosuquidar, laniquidar and ONT-093) show high potency and specificity for P-gp. The continued development of these agents may establish the true therapeutic potential of Pgp- mediated MDR reversal.Multipla rezistencija na lekove (multidrug resistance, MDR) predstavlja značajnu prepreku u primeni efektivne terapije za mnoge pacijente koji su oboleli od različitih tipova kancera. Mada rezistencija na antikancerogene lekove može da nastane usled dejstva različitih mehanizama, klasična multipla rezistencija je uglavnom povezana sa povećanom ekspresijom P-glikoproteina (P-gp) koji deluje kao pumpa za izbacivanje (engl. efflux pump) različitih supstrata iz ćelije, što dovodi do smanjenja koncentracije antikancerogenih lekova u tumorskoj ćeliji. Inhibicija P-gp kao mogućnost prevazilaženja rezistencije je dosta proučavana poslednjih godina. U ovom radu prikazan je razvoj P-gp inhibitora od prve do treće generacije. Upotreba prve generacije inhibitora, kao što su ciklosporin A i verapamil, ograničena je zbog njihove toksičnosti, dok je druga generacija inhibitora, kojoj pripadaju valspodar i birikodar, pokazala smanjenu toksičnost, ali i neočekivane farmakokinetičke interakcije sa antikancerogenim lekovima, kao i sa drugim transportnim proteinima. Treća generacija inhibitora (tarikvidar, zosukvidar, lanikvidar i ONT-093) pokazala je veliku aktivnost i specifičnost za P-gp. Dalji razvoj ovih lekova predstavlja značajan terapijski potencijal za prevazilaženje rezistencije na antikancerogene lekove

Skrining konstituenata etarskog ulja Satureja montana u potencijalnom lečenju COVID 19 primenom kompjuterskih metoda

Constituents of essential oil of Satureja Montana (SM) were investigated in aim of elucidation of potential activities on viruses that can be transcribed in genetic material, such are SARS CoV 2 and HIV. Chemical structures of constituents (34) of the SM essential oil were built and geometry optimized using ChemDraw ultra 8.0 and Chem3D Pro 8.0 programs. Prediction of potential interactions for each constituents with large number of targets was performed by SwissTargetPrediction program. Results indicate that constituents, with certain level of probability, can be involved in interactions with some targets significant for antiviral activity, in direct or indirect mode, such are adenosine receptors type 1, UDP- glukuronosyltransferases, receptor-dependent transport channels, peroxisome-proliferator activated receptor alpha, GLI 2, as well as some other targets. Since in this work just constituents of SM essential oil were investigated, further studies should be directed towards investigation of full content of SM, in various solvents, for elucidation of mechanisms of action of this plant in therapy of viremias, presumably for supposed inhibition of transcription of viruses.Konstituenti esencijalnog ulja Satureja Montana (SM) ispitivani su u cilju razjašnjenja njihovog potencijalnog delovanja na viruse koji se mogu inkorporirati u genetski materijal, kao što su SARS CoV 2 i HIV. Hemijske strukture konstituenata (34) esencijalnog ulja SM su prikazane i optimizovane korišćenjem programa ChemDraw ultra 8.0 i Chem3D Pro 8.0. Predviđanje potencijalnih interakcija za svaki konstituent sa velikim brojem bioloških targeta izvršeno je u programu SwissTargetPrediction. Rezultati ukazuju na to da konstituenti, sa odgovarajućom predviđenom verovatnoćom, stupaju u interakcije sa određenim targetima koji mogu biti od značaja za dejstvo na viruse na posredan ili neposredan način, od kojih su najznačajniji adenozinski receptor tipa 1, UDP-glukuronozil transferaza, receptor-zavisni transportni kanali, alfa receptor aktiviran proliferatorom peroksizoma, GLI 2, kao i neki drugi targeti. S obzirom da su u ovom radu ispitivani samo konstitenti esencijalnog ulja SM, potrebno je izvršiti dodatne studije konstituenata ukupnog sadržaja SM, u različitim rastvaračima, radi sagledavanja potencijala ove lekovite biljke u terapiji viremija, pre svega pretpostavljenoj inhibiciji transkripcije virusa.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Računarski modeli za predviđanje transporta lekova posredovanog P-glikoproteinom

P-glycoprotein (Pgp) is a transmembrane transporter which can, by transporting structurally diverse compounds, influence the absorption, distribution and efficacy of a number of drugs. Pgp overexpression in cells is a major contributing factor to the development of drug resistance. For these reasons, potential for compound efflux by Pgp should be assessed early on in the drug discovery process, preferably even prior to compound synthesis. To meet this demand, numerous computational models have been developed during the past decade, capable of predicting Pgp-mediated transport based solely on chemical structures. This paper summarizes the various approaches that have been used for model development, discusses their advantages and disadvantages and focuses on key factors that influence model reliability. The promiscuous nature of the transport can be seen as a major challenge for most computational chemistry methods. Nevertheless, the attained level of accuracy of literature models suggests that they can be useful in the drug discovery setting. Greater availability of experimental data and integration of predictions made by different modeling methods has the potential to further improve the reliability of computational predictions.P-glikoprotein (Pgp) je transmembranski transporter koji, transportujući strukturno raznovrsne lekove iz unutrašnjosti ćelije u ekstracelularnu sredinu, može uticati na resorpciju, distribuciju i efikasnost većeg broja lekova. Prekomerna ekspresija Pgp-a u ćelijama predstavlja jedan od mehanizama razvoja rezistencije na lekove. Iz ovih razloga, potrebno je u ranoj fazi otkrića leka predvideti da li je potencijalni lek supstrat za Pgp, idealno i pre same sinteze. U tu svrhu, tokom poslednje decenije razvijen je veliki broj računarskih modela koji omogućavaju predviđanje transporta posredstvom Pgp-a samo na osnovu hemijske strukture. U ovom radu prikazan je pregled različitih pristupa koji su korišćeni u razvoju modela, razmotrene su njihove prednosti i nedostaci, kao i faktori koji u najvećoj meri utiču na pouzdanost predviđanja. Polispecifičnost ovog transportera predstavlja značajan izazov za većinu metoda računarske hemije. Ipak, dostignut nivo tačnosti modela koji su prikazani u litearaturi ukazuje na činjenicu da oni mogu doprineti racionalizaciji procesa dizajniranja novih lekova. Šira dostupnost eksperimentalnih podataka, kao i kombinovanje različitih pristupa modelovanju transporta, mogu dodatno unaprediti postojeće modele

An austempering study of ductile iron alloyed with copper

Austempered ductile iron (ADI) has proved to be an excellent material as it possesses attractive properties: high strength, ductility and toughness are combined with good wear resistance and machinability. These properties can be achieved upon adequate heat treatment which yields the optimum microstructure for a given chemical composition. In this paper the results of an investigation the austempering of ADI alloyed with 0.45 % Cu for a range of times and temperatures are reported. The microstructure and fracture mode developed throughout these treatments have been identified by means of light and scanning electron microscopy and X-ray diffraction analysis. It was shown that the strength, elongation and impact energy strongly depend on the amounts of bainitic ferrite and retained austenite. Based on these results, and optimal processing window was established

Computational study of interactions of Cannabis Sativa constituents with potential epigenetic targets involved in processes of multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease, which treatment requires better understanding of underlying pathological processes. Epigenetic alterations as to some extent reversible processes might serve as another target for the therapy of MS for the aim of reprogramming inherited, environ-mentally initiated or by developing processes of MS influenced genotype and fenotype. Cannabis sativa (CS) has been experimentally proven for positive outputs in treatment of MS, not just in elevating symptoms, but stopping the progress of disease. However, incidences of healing might focus further attention of wider impact of numerous constituents of CS that might play various roles in whole processes of possible healing, including epigenetic modulation. There are the proofs however that epigenetic changes are involved at certain stages of MS. In this work, the potential of CS for treatment of altered epigenetic mechanisms involved in MS was investigated using network pharmacology methods. Constituents of CS were collected from literature, classified in few classes: cannabinoids, terpenoids, flavonoids, stilbenoids and alkaloids. Epigenetic targets (37) were chosen as overlap of predicted epigenetic targets for CS constituents by SwissTargetPrediction and EpigeneticTargetPro-filer, as well as epigenetic targets involved in MS obtained from GeneCArds and DisGeNet data bases. The relevance of chosen targets is supported in literature, as asscosiated with various processes of MS. Network of CS constituents and chosen targets was mapped and analyzed by Cytoscape 3.9.1. Among the network consisted of 71 nodes and 266 edges, 266 interactions between CS constituents and epigenetic targets were indicated. The degree analysis of the obtained netwok was performed from the aspect of particular compound for possible targets and particular target for possible compounds interactions. Predictions of compunds and targets interactions are based on molecular similarity, therefore it remains to be further explored are those possible interactions associated with agonistic or antagonistic effects of the compounds. Promising results regarding possible interactions of CS constituents on epigenetic level of MS processes might be helpful for consideration of the therapy by this medical plant at various stages of MS development, taking into account other possible interactions with targets out of epigenetic landscape, associated with MS as well.10th IAPC Meeting, Book of Abstract

Elucidation of molecular mechanisms of activity of Echinacea spp. constituents for possible treatment of COVID 19 by computer-aided methods

Echinacea spp. have long history of use, dating from American natives. Among ten, three species (Echinacea purpurea (L.), Echinacea pallida (Nutt.) and Echinacea angustifolia (DC.)), are the most used, alone or in mixes, for treatment of various conditions, such are infections, cancers etc. Recently, it was shown that Echinacea spp. are effective in treatment of COVID 19, inhibiting progress of SARS CoV2 development. Due to availability of structures of certain number of chemical constituents of Echinacea spp. and 3D structures of possible targets included in processes of interaction, elucidation of its molecular mechanisms of action was performed by computational methods. Three approaches for evaluation of molecular mechanisms of Echinacea spp. constituents (24 from Echinacea purpurea and 10 from other Echinacea spp.) for possible treatment of recent COVID 19 pandemia are presented. First, docking studies of Echinacea spp. constituents (34) were performed on three targets, according to literature as the most important for SARS CoV2 virus spread and development: SARS CoV2 spike protein and angiotensin converting enzyme (ACE2) receptor responsible for virus entry, as well as SARS-CoV-2 metalloproteinase Mpro as the most responsible in mediation of viral transcription and replication. Second, physicochemical properties and pharmacokinetic-related characterization (Lipinksi Rule of five) of Echinacea spp. constituents in conformation with minimum energy, were performed by Data Warrior program. Results show that 4/34 compounds have negative values of log P (hydrophilic), 6/34 showed negative results regarding selection by Rule of five, among which 5 significantly differ in H-bonding capacity, which indicates different properties for oral absorption and distribution within the organism, as well as mode of action. Drug likeness, calculated for fragments of 34 constituents, is scattered within 15 units of difference. Third, the probability of interaction of Echinacea spp. constituents with targets was estimated by use of SwissTarget Prediction program, based on query molecule showing activity on certain class of targets. Results showed that cannabinoid receptors (CNR) 1 and 2 (17 and 16 units) and peroxisome proliferatoractivated receptor gamma (PPARγ) (15 units) are the most preferable targets for interactions. Possible molecular mechanisms involved in evidented pharmacological records in treatment of COVID 19 by Ehinacea spp. were elucidated with regard of results of all three methods.10th IAPC Meeting, Book of Abstract

Stereohemijski aspekti dejstva i farmakokinetike lekova

The action and fate of drugs in the organism are determined by their interactions with endogenous macromolecules which are predominantly chiral in character. Consideration of the stereochemical aspects of drug action and pharmacokinetics has been intensified since the 1980s and has led to extensive documentation of significant differences existing between stereoisomeric forms of a single drug. Enantiomers can posses different efficacies, exhibit different pharmacological and toxicological effects, and consequently be characterized by different safety profiles. The growing wealth of evidence on the importance of stereochemistry, regulatory incentives, development of asymmetric synthesis methods and analytics - all contributed to fundamental changes in the way new chiral drugs are developed, tested, registered and market-managed. Today, enantiomers need to be treated as separate chemical entities and investigated correspondingly. Development of single enantiomer drugs can facilitate the reduction of total dose of xenobiotic administered to patients; improve the accuracy of doseresponse estimation; simplify pharmacokinetic studies and therapeutic monitoring. The stereochemical characteristics of biologically active compounds should, therefore, be considered from the earliest stages of drug development. Based on the established impact of stereochemistry, a single enantiomer formulation should be favored, whenever justified.Dejstvo i sudbina leka u organizmu zavise od hiralnosti samih lekova kao i endogenih makromolekula sa kojima stupaju u interakciju. Razmatranje stereohemijskih aspekata dejstva i farmakokinetike lekova intenzivirano je početkom 80-tih godina prošlog veka i doprinelo je opsežnom dokumentovanju značajnih razlika između stereoizomernih oblika jednog leka. Enantiomeri tako mogu posedovati različitu efikasnost, mogu ispoljavati drugačije farmakološke i toksikološke efekte i sledstveno mogu imati različite bezbednosne profile. Sve veći broj dokaza o važnosti stereohemije, podsticaji regulatornih agencija, razvoj metoda asimetrične sinteze i analitike - doveli su do suštinskih promena u načinu na koji se novi hiralni lekovi razvijaju, ispituju, registruju i tržišno plasiraju. Enantiomere je danas neophodno tretirati kao zasebne entitete i zasebno ih ispitivati. Razvoj enantiomerno čistih formulacija lekova može omogućiti smanjenje ukupne količine ksenobiotika kojoj se pacijent izlaže, omogućiti precizniju procenu odnosa doze i efekta, pojednostaviti farmakokinetička ispitivanja i terapijski monitoring. Stoga je stereohemijske osobine biološki aktivnih jedinjenja neophodno razmatrati od najranijih faza procesa stvaranja novog leka da bi se blagovremeno napravio racionalan izbor jednog enantiomera za terapijsku primenu, kad god je to opravdano