QSAR Modeling of Antifungal Activity of Some Heterocyclic Compounds

QSAR analysis of a set of benzoxazoles, benzimidazoles, oxazolo[4,5-b]pyridines and benzothiazoles, showing growth inhibitory activity against Candida albicans, was performed using a multiple regression procedure. Topological indices (TIs) and principal component analysis (PCA) on TIs were used in modeling antifungal activity. Selection of TIs relevant to developing QSAR models was made using the largest PC factor loading scores. Correlation coefficient 0.97 obtained in the validation procedure indicated the excellent quality of the derived QSAR models

NETWORK INFERENCE DRIVEN DRUG DISCOVERY

The application of rational drug design principles in the era of network-pharmacology requires the investigation of drug-target and target-target interactions in order to design new drugs. The presented research was aimed at developing novel computational methods that enable the efficient analysis of complex biomedical data and to promote the hypothesis generation in the context of translational research. The three chapters of the Dissertation relate to various segments of drug discovery and development process. The first chapter introduces the integrated predictive drug discovery platform „SmartGraph”. The novel collaborative-filtering based algorithm „Target Based Recommender (TBR)” was developed in the framework of this project and was validated on a set of 28,270 experimentally determined bioactivity data points involving 1,882 compounds and 869 targets. The TBR is integrated into the SmartGraph platform. The graphical interface of SmartGraph enables data analysis and hypothesis generation even for investigators without substantial bioinformatics knowledge. The platform can be utilized in the context of target identification, drug-target prediction and drug repurposing. The second chapter of the Dissertation introduces an information theory inspired dynamic network model and the novel “Luminosity Diffusion (LD)” algorithm. The model can be utilized to prioritize protein targets for drug discovery purposes on the basis of available information and the importance of the targets. The importance of targets is accounted for in the information flow simulation process and is derived merely from network topology. The LD algorithm was validated on 8,010 relations of 794 proteins extracted from the Target Central Resource Database developed in the framework of the “Illuminating the Druggable Genome” project. The last chapter discusses a fundamental problem pertaining to the generation of similarity network of molecules and their clustering. The network generation process relies on the selection of a similarity threshold. The presented work introduces a network topology based systematic solution for selecting this threshold so that the likelihood of a reasonable clustering can be increased. Furthermore, the work proposes a solution for generating so-called “pseudo-reference clustering” for large molecular data sets for performance evaluation purposes. The results of this chapter are applicable in the lead identification and development processes

BioR the treatment of deep majuscule caries and some forms of pulpits

Rezumat. Cercetările clinice realizate prin tratamentul a 196 dinţi afectaţi de carie şi pulpită acută focară la 155 pacienţi (grupa martor a fost medicată cu Calcium Hydroxide, iar cea de experienţă cu BioR) au apreciat Bior-ul ca biopreparat net superior cu capacităţi de menţinere a vitalităţii şi integrităţii organului pulpar.Summary. Clinical studies in the treatment of 196 cases of caries and acute focal pulpits (135 patients of which the witness group treated with Calcium Hydroxide and the trial groups with BioR) showed BioR to be definitely superior and capable of maintaining the vitality and integrity of the pulpal organ

Current status of the Mechanical Ventilation in ICU

Catedra Anesteziologie si Reanimatologie №1 USMF “Nicalae Testemiţanu”Actualy, as a result of development of technology and medicine, mechanical ventilation of the lungs (MV), even if it is prolonged, it is an everyday occurrence in ICU (Intensive Care Unit). Nevertheless, the MV is one of the most important and unsolved problems in critical care medicine [1]. In our article we have studied variety aspects of its use in intensive care practice: indications, protective lung ventilation strategy, patient-ventilator synchronization, application of tracheostomy, and description of our experience. La momentul actual datorită progresului tehnic şi medical, atât ventilaţia artificială pulmonară (VAP) cât şi VAP prelungit este un lucru obişnuit în secţia de terapie intensivă (TI). Totuşi VAP rămâne una din cele mai importante teme de dezbateri în TI [1]. În articolul nostru am studiat o multitudine de aspecte legate de VAP: indicaţii, strategia de ventilaţia mecanica protectiva, sincronizarea pacient-ventilator, traheostomia

Some results of preventive endodontic treatment performed by practising dentists

Catedra Stomatologie Terapeutică FPM USMF „Nicolae Testemiţanu”The analysis of endodontic treatment results of 186 teeth (46 monoradicular and 140 pluriradicular) performed by practising dentists have shown a lot of errors followed by severe local and general complications are still made: roof undermining – 48.3%, step development in the canal – 23.35%, endodontic instruments fractures in the apical and middle third of canal – 9.7%, periodontal mechanical and chemical lesions – 16.5%, periapical endodontic accidents – 5.9%, 2 cases of neuropathy of the lower alveolar nerve and vertical root fractures – 3.2%. Analiza rezultatelor tratamentului endodontic a 186 de dinţi (46 monoradiculari şi 140 pluriradiculari) efectuat de medicii stomatologi practici a demonstrat că sunt comise încă multe erori сu consecinţe grave locale şi generale: subminări de tavan- 48,3%; apariţie de trepte pe canal – 23,35%; 9,7% de fracturi de instrumente endodontice în treimea medie şi apicală de canal; 16,5% de traumatizme mecanice şi chimice periodontale; 5,9% de accidente endodontice periapicale şi 2 cazuri de neuropatie a nervului alveolar inferior; 3,2% de fracturări verticale de rădăcină etc

Omega Polynomial in Tubular Nanostructures

A new counting polynomial, called the »Omega« Ω(G, x) polynomial, was recently proposed by Diudea on the ground of quasi-orthogonal cut »qoc« edge strips in a polycyclic graph. Within a qoc, not all cut edges are necessarily orthogonal, meaning not all are pairwise codistant. Two topological indices: CI (Cluj-Ilmenau), eventually equal to the well-known PI index, in planar, bipartite graphs, and IΩ are defined on the newly proposed polynomial and exemplified. Closed analytical formulas for Ω(G, x) and CI in polyhex tori and tubes are given

TIN-X:target importance and novelty explorer

Abstract Motivation The increasing amount of peer-reviewed manuscripts requires the development of specific mining tools to facilitate the visual exploration of evidence linking diseases and proteins. Results We developed TIN-X, the Target Importance and Novelty eXplorer, to visualize the association between proteins and diseases, based on text mining data processed from scientific literature. In the current implementation, TIN-X supports exploration of data for G-protein coupled receptors, kinases, ion channels, and nuclear receptors. TIN-X supports browsing and navigating across proteins and diseases based on ontology classes, and displays a scatter plot with two proposed new bibliometric statistics: Importance and Novelty. Availability and Implementation http://www.newdrugtargets.org </jats:sec

A Potent and Selective Inhibitor of Cdc42 GTPase

Cdc42, a member of the Rho family of GTPases, has been shown to play a role in cell adhesion, cytoskeletal arrangement, phagocytosis and cell motility and migration, in addition to a host of other diverse biological processes. The function of Rho-family GTPases in disease pathogenesis has been well established and identification of small, cell permeable molecules that selectively and reversibly regulate Rho GTPases is of high scientific and potentially therapeutic interest. There has been limited success in identifying inhibitors that specifically interact with small Rho family GTPases. The identified probe, ML141 (CID-2950007), is demonstrated to be a potent, selective and reversible non-competitive inhibitor of Cdc42 GTPase suitable for in vitro assays, with low micromolar potency and selectivity against other members of the Rho family of GTPases (Rac1, Rab2, Rab7). Given the highly complementary nature of the function of the Rho family GTPases, Cdc42 selective inhibitors such as those reported here should help untangle the roles of the proteins in this family

Characterization of a Cdc42 Protein Inhibitor and Its Use as a Molecular Probe

Cdc42 plays important roles in cytoskeleton organization, cell cycle progression, signal transduction, and vesicle trafficking. Overactive Cdc42 has been implicated in the pathology of cancers, immune diseases, and neuronal disorders. Therefore, Cdc42 inhibitors would be useful in probing molecular pathways and could have therapeutic potential. Previous inhibitors have lacked selectivity and trended toward toxicity. We report here the characterization of a Cdc42-selective guanine nucleotide binding lead inhibitor that was identified by high throughput screening. A second active analog was identified via structure-activity relationship studies. The compounds demonstrated excellent selectivity with no inhibition toward Rho and Rac in the same GTPase family. Biochemical characterization showed that the compounds act as noncompetitive allosteric inhibitors. When tested in cellular assays, the lead compound inhibited Cdc42-related filopodia formation and cell migration. The lead compound was also used to clarify the involvement of Cdc42 in the Sin Nombre virus internalization and the signaling pathway of integrin VLA-4. Together, these data present the characterization of a novel Cdc42-selective allosteric inhibitor and a related analog, the use of which will facilitate drug development targeting Cdc42-related diseases and molecular pathway studies that involve GTPases.This work was supported by National Science Foundation (NSF) Grant MCB0956027 and National Institutes of Health Grant R03 MH081231-01 from the Molecular Libraries Program (to A. W. N.); University of New Mexico Center for Molecular Discovery Molecular Libraries Probe Production Centers (UNMCMD MLPCN) National Institutes of Health Grants U54MH084690 and R01HL081062 (to L. A. S.); UNM National Center for Research Resources (NCRR) Grant 5P20RR016480 (to L. G. H.); National Institutes of Health Grant R21 CA170375-01 through the NCI (to A. W. N., L. G. H., and J. E. G.); National Institutes of Health Grants NS066429 and AI092130 (to T. B.); and University of Kansas Specialized Chemistry Center (KUSCC) MLPCN National Institutes of Health Grant U54HG005031 (to J. A.)

Identification of a small molecule yeast TORC1 inhibitor with a flow cytometry-based multiplex screen

TOR (target of rapamycin) is a serine/threonine kinase, evolutionarily conserved from yeast to human, which functions as a fundamental controller of cell growth. The moderate clinical benefit of rapamycin in mTOR-based therapy of many cancers favors the development of new TOR inhibitors. Here we report a high throughput flow cytometry multiplexed screen using five GFPtagged yeast clones that represent the readouts of four branches of the TORC1 signaling pathway in budding yeast. Each GFP-tagged clone was differentially color-coded and the GFP signal of each clone was measured simultaneously by flow cytometry, which allows rapid prioritization of compounds that likely act through direct modulation of TORC1 or proximal signaling components. A total of 255 compounds were confirmed in dose-response analysis to alter GFP expression in one or more clones. To validate the concept of the high throughput screen, we have characterized CID 3528206, a small molecule most likely to act on TORC1 as it alters GFP expression in all five GFP clones in an analogous manner to rapamycin. We have shown that CID 3528206 inhibited yeast cell growth, and that CID 3528206 inhibited TORC1 activity both in vitro and in vivo with EC50s of 150 nM and 3.9 μM, respectively. The results of microarray analysis and yeast GFP collection screen further support the notion that CID 3528206 and rapamycin modulate similar cellular pathways. Together, these results indicate that the HTS has identified a potentially useful small molecule for further development of TOR inhibitors