Dissertations / Theses on the topic 'Master of Drug Discovery and Development'
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Cai, Xiaoshu. "DEVELOPMENT OF COMPUTATIONAL APPROACH FOR DRUG DISCOVERY." Case Western Reserve University School of Graduate Studies / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case1465403528.
Full textGage, Zoe O. "Interferon, viruses and drug discovery." Thesis, University of St Andrews, 2017. http://hdl.handle.net/10023/10127.
Full textCereto, Massagué Adrià. "Development of tools for in silico drug discovery." Doctoral thesis, Universitat Rovira i Virgili, 2017. http://hdl.handle.net/10803/454678.
Full textEl cribado virtual es un método quimioinformático que consiste en la criba de moléculas bioactivas de grandes bases de datos de moléculas pequeñas. Esto permite a los investigadores ahorrarse el coste de probar experimentalmente cientos o miles de compuestos candidatos, reduciéndolos hasta cantidades manejables. Para la validación de los métodos de cribado virtual hacen falta bibliotecas de moléculas señuelo. El software DecoyFinder fue desarrollado como aplicación gráfica de fácil uso para la construcción de bibliotecas de moléculas señuelo, y fue posteriormente ampliado con los hallazgos de investigación posterior sobre la construcción i rendimiento de bibliotecas de moléculas señuelo. El Protein Data Bank (PDB) es muy útil porque proporciona estructuras tridimensionales para complejos proteina-ligando, y por tanto, información sobre como interactúan. Para los métodos de cribado virtual que dependen de ellas, es extremadamente importante su fiabilidad. VHELIBS fue desarrollado como herramienta para inspeccionar e identificar, fácil e intuitivamente, las estructuras fiables del PDB, basándose en como de bueno es su encaje con sus correspondientes mapas de densidad electrónica. Mientras que el cribado virtual intenta encontrar nuevas moléculas bioactivas para determinadas dianas, el enfoque inverso también se utiliza: a partir de una molécula, buscar dianas donde presente actividad biológica no documentada. Este cribado inverso es conocido en inglés como “in silico target fishing”, o pesca de dianas “in silico”, y es especialmente útil en el ámbito de la reutilización de fármacos. Al comenzar esta tesis, no había ninguna plataforma de “target fishing” de libre acceso, y aunque durante los años se han desarrollado algunas, en todos los casos su predicción de bioactividad es cualitativa. Por eso se desarrolló una plataforma propia de “target fishing” de libre acceso, con la implementación de un nuevo método que proporciona la primera predicción cuantitativa de bioactividad para este tipo de plataforma.
Virtual screening is a cheminformatics method that consists of screening large small-molecule databases for bioactive molecules. This enables the researcher to avoid the cost of experimentally testing hundreds or thousands of compounds by reducing the number of candidate molecules to be tested to manageable numbers. For their validation, virtual screening approaches need decoy molecule libraries. DecoyFinder was developed as an easy to use graphical application for decoy library building, and later updated after some research into decoy library building and their performance when used for 2D similarity approaches. The Protein Data Bank (PDB) is very useful because it provides 3D structures for protein-ligand complexes and, therefore, information on how certain ligands bind and interact with their targets. For virtual screening apporaches relying on these structures, it is of the utmost importance that the data available on the PDB for the ligand and its binding site are reliable. VHELIBS was developed as a tool to easily and intuitively inspect and identify reliable PDB structures based on the goodness of fitting between ligands and binding sites and their corresponding electron density map. While virtual screening aims to find new bioactive molecules for certain targets, the opposite approach is also used: starting from a given molecule, to search for a biological target for which it presents previously undocumented bioactivity. This reverse screening is known as in silico or computational target fishing or reverse pharmacognosy, and it is specially useful for drug repurposing or repositioning. When this thesis was started, there were no freely available target fishing platforms, but some have been developed during the years. However, they are qualitative in the nature of their activity prediction, and thus we set out to develop a freely accessible target fishing web service implementing a novel method which provides the first quantitative activity prediction: Anglerfish.
Acoca, Stephane. "In silico methods in drug discovery and development." Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=110376.
Full textLes méthodes the modélisation sont devenues un outil inestimable dans le processus de découverte et de développement de nouveaux médicaments. Au cours de cette thèse va être décrit le développement et l'application de méthodes utilisés à chaque stage de la découverte et du développement de produits pharmaceutiques. Le Chapitre 2 est un aperçu sur l'utilisation de méthodes computationnelles vers le développement de deux nouveaux inhibiteurs des protéines Bcl-2, Obatoclax et ABT-737, en développement pour le traitement du Cancer. L'étude propose certains mécanismes d'ABT-737 qui expliquent ca sélectivité envers les membres de la famille Bcl-2. De plus, nous proposons un mécanisme d'attachement pour Obatoclax qui conforme aux données expérimentales. Le Chapitre suivant adresse l'utilisation du dépistage virtuel pour l'identification de nouvelles molécules mère. La Ligase de l'Edition d'ARN du Trypanosoma brucei a été choisie comme cible pour le développement de traitements contre des infections dû au Trypanosome et C35 a été identifié comme nouvel inhibiteur de l'enzyme. En outre, notre recherche démontre que l'action de C35 s'étends a l'inhibition de plusieurs enzymes nécessaires pour le mécanisme d'édition de l'ARN en plus de compromettre l'intégrité du complexe multi-protéinique qui l'effectue. Le Chapitre suivant prends regard a l'utilisation de donnes dérivant de la spectrométrie de masse pour but d'accélérer la découverte de molécules bioactives venant de sources naturelles. Nous avons développé un algorithme qui analyse les données MS/MS pour but de dériver la formule moléculaire du composé. Le nouvel algorithme a obtenu un taux de succès s'élevant à 95% sur un ensemble test de 91 molécules. Le dernier Chapitre de la thèse explore l'utilisation de simulations de dynamique moléculaire pour générer en ensemble conformationel de protéines cible pour son utilisation dans le dépistage virtuel. Les ensembles conformationel ont étés généré pour une série test obtenu d'un répertoire attitré 'Directory for Useful Decoys'. Les résultats démontrent que les ensembles conformationel dérivés de la dynamique moléculaire ont apporté des améliorations remarquables sur deux des cibles testées dû à une capacité accrue de placement approprié des molécules dans un site qui est autrement très restreint. Le dernier Chapitre de cette thèse est une discussion générale sur le travail accomplie et une proposition sur la manière dont tous les éléments sont intégrer dans un protocole de découverte et de développement de produits pharmaceutiques.
Hoffman, Benjamin. "The Genetics of Cancer in Pharmacological Drug Development." Diss., Temple University Libraries, 2011. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/212455.
Full textPh.D.
The field of cancer therapeutic development has been dominated by two research and discovery paradigms, the cytotoxicity-based or phenotype driven strategy and the target-based rational approach. This thesis describes the standardization of novel assays used in both approaches and the discoveries made using these processes. Rational drug design or the target-based approach to discovering novel anti-cancer agents requires a basic understanding of the oncogenic signals that induce uncontrolled cellular proliferation. c-MET is a proto-oncogene, linked to a number of different cancers, that encodes a receptor tyrosine kinase. As an oncogene, c-MET has been shown to transform cells in the laboratory setting and is dysregulated in number of malignancies. Thus, we sought to discover a small molecule inhibitor of c-MET kinase activity by screening a novel library of small molecules. In the second part of this dissertation, we describe the standardization of a high-throughput assay to identify putative c-MET inhibitors and the results of our screening attempt. Cytotoxicity-based screening is another validated approach that is used to discover anti-cancer agents. As a parallel program to our c-MET discovery effort, we designed a high-throughput cytotoxicity assay to identify a novel small molecule with high cytotoxic activity towards tumor cells. The result of this screen was the identification of ON015640, a novel anti-cancer therapeutic with tubulin-depolymerizing activity. Throughout the course of this project, we tried to discern the advantages and disadvantages of the two predominant paradigms in cancer therapeutic research. Both strategies require careful assay design and an acute understanding of the molecular and genetic underpinnings of cancer. While it is clear that structure-based rational drug design has its merits and its success stories, it has become increasingly clear that seeking out a desired biological effect may serve as a more effective staring point when dealing with cancers for which no clear oncogene addiction phenotype has been observed.
Temple University--Theses
Schreiber, Kimberly C. M. "Assay development for use in drug discovery against Bovine Trichomoniasis." Scholarly Commons, 2007. https://scholarlycommons.pacific.edu/uop_etds/650.
Full textMiller, Lisa Margaret. "The development of small molecule inhibitors for fibrosis drug discovery." Thesis, University of Strathclyde, 2016. http://digitool.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=27922.
Full textHatherley, Rowan. "Structural bioinformatics studies and tool development related to drug discovery." Thesis, Rhodes University, 2016. http://hdl.handle.net/10962/d1020021.
Full textYamaura, Kei. "Novel methods for drug discovery and development using ligand-directed chemistry." 京都大学 (Kyoto University), 2016. http://hdl.handle.net/2433/217177.
Full textPilger, Jens. "Development and application of NMR methods for challenges in drug discovery." Doctoral thesis, Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2013. http://hdl.handle.net/11858/00-1735-0000-0015-C6E8-4.
Full textAldhumani, Ali Hamed. "Pharmacophore Model Development: Targeting Noncoding RNA for Antibacterial/Antiviral Drug Discovery." Ohio University / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1610705872573225.
Full textGrace, Christopher Philip. "Detection and exploitation of expression QTL in drug discovery and development." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:7b174e64-d17f-4e2c-b366-065684bfd813.
Full textPevzner, Yuri. "Development and application of web-based open source drug discovery platforms." Scholar Commons, 2015. https://scholarcommons.usf.edu/etd/5550.
Full textStelzhammer, Viktoria. "Major depressive disorder : molecular profiling to aid drug target discovery." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607830.
Full textÁlvarez, García Daniel. "Protein solvation preferences: applications to drug discovery." Doctoral thesis, Universitat de Barcelona, 2014. http://hdl.handle.net/10803/285451.
Full textEl diseño de fármacos asistido por ordenador es actualmente un actor fundamental en el proceso de descubrimiento de nuevos fármacos. Las aproximaciones basadas en estructura usan la información estructural de la Diana terapéutica para proponer moléculas activas y seguras. Sin embargo, el proceso dista de ser sencillo y nuevas metodologías están continuamente siendo investigadas para solventar las limitaciones actuales, siendo la flexibilidad de la diana y el tratamiento y la estructura del agua en la cavidad, dos factores usualmente obviados o simplificados. Como ha sido demostrado por varios experimentos de NMR y cristalografía, moléculas pequeñas de solventes orgánicos (p.e. etanol, acetamida o acetonitrilo), son capaces de identificar sitios de unión y proporcionan pistas para el diseño racional de nuevas moléculas bioactivas. MDmix es un método basado en simulación molecular que explota dicho fenómeno in silico. Usando mezclas de moléculas orgánicas pequeñas y agua, cada una con propiedades químicas diferentes, se identifican mapas energéticos de interacción sobre la superficie de la diana. Esta información nos permite identificar sitios de unión para ligandos y caracterizar dicha interacción para guiar el proceso de identificación de hits y la optimización de cabezas de serie. El trabajo presentado en esta tesis se puede dividir en dos publicaciones principales: En la primera, el efecto de la flexibilidad de la diana es estudiado para establecer unas guías de actuación a la hora de simular el sistema. Encontramos que la flexibilidad es fundamental a la hora de identificar cavidades inducidas o con alto grado de flexibilidad pero, a la vez, la interpretación de los resultados es mucho más compleja cuando hay cambios conformacionales. Por otra banda, aplicando restricciones suaves a la movilidad de los átomos, se gana reproducibilidad en los resultados y los errores en la estimación energética son mínimos. En la segunda publicación, se estudió el uso de diferentes mezclas de solventes para la identificación de farmacóforos experimentales en dos sistemas test (heat shock protein 90 y HIV proteasa 1). El tratamiento explícito del agua proporciona mapas energéticos capaces de identificar correctamente los puntos de interacción más favorables con una precisión sin precedentes cuando se compara con otros métodos. Además, demostramos como los mapas energéticos obtenidos para las moléculas de agua son capaces de discernir entre aguas desplazables y no desplazables por un potencial ligando. La información extraída de dichos mapas puede ser de alta utilidad para guiar la identificación de nuevas moléculas activas y para la optimización de la potencia de ligandos ya identificados. Finalmente, se presenta un programa de código abierto escrito en python cuyo objetivo es facilitar el uso de la metodología así como su adopción en cualquier proyecto de diseño de fármacos. En el capítulo final se discuten posibles mejoras y aplicaciones prácticas del método en proyectos actualmente en investigación y direcciones futuras a seguir. MDmix, siendo un método basado en simulación molecular, permite incorporar la flexibilidad de la diana y tratar explícitamente el efecto del solvente. Por ello, ofrece ventajas significativas sobre aproximaciones tradicionales en la identificación de sitios de unión y su caracterización. Siendo aplicable sobre cualquier diana, aún sin conocimiento previo, ofrece una nueva alternativa en el siempre desafiante proceso del diseño de fármacos.
Mohiddin, Syed Basha. "Development of novel unsupervised and supervised informatics methods for drug discovery applications." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1138385657.
Full textHara, Takuji. "Innovation in the pharmaceutical industry : the process of drug discovery and development /." Cheltenham [u.a.] : Elgar, 2003. http://www.gbv.de/dms/bs/toc/357041208.pdf.
Full textBalfer, Jenny [Verfasser]. "Development and Interpretation of Machine Learning Models for Drug Discovery / Jenny Balfer." Bonn : Universitäts- und Landesbibliothek Bonn, 2015. http://d-nb.info/1080561374/34.
Full textMohiddin, Syed B. "Development of novel unsupervised and supervised informatics methods for drug discovery applications." The Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=osu1138385657.
Full textSchreyer, Adrian Michael. "Characterisation of protein-ligand interactions and their application to drug discovery." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609324.
Full textGómez, Tamayo Jose Carlos. "Development and application of computational techniques to drug discovery and structure-function relationships." Doctoral thesis, Universitat Autònoma de Barcelona, 2016. http://hdl.handle.net/10803/400278.
Full textThis thesis present the results of various computational techniques applied to the complex world of drug development with a particular focus to its application to one of the most important membrane protein family, the GPCRs. The thesis is organized in the following sections: introduction, methods, objectives, results and conclusion. Introduction: covers the fundamentals of G-protein coupled receptors molecular biology; classification, structure, pharmacology, signaling and activation. Methods: describes the computational techniques used in the thesis. Results: In this section, the results obtained are presented. A first paragraph contextualizes all the work done, describing its objectives, stating the contribution of the author; moreover a brief introduction of each part of the results paragraphs. The following subsections contain a detailed explanation of all projects done in this thesis. Projects: LigandFinder This web application provides a user-friendly way to perform fast virtual screening to find new compounds similar to a set of compounds of known structure. It explores the chemical space of a database with more than 20M compounds. To our knowledge, LigandFinder is the first virtual screening web application able to use several ligands as input. Sulfur-containing amino acids study In this work the interactions of sulfur-containing amino acids (cysteine and methionine) in membrane proteins are studied. A refined crystal structures database is screened in order to find interactions of sulfur-containing residues with themselves and other residues. These interactions are clustered, and the interaction energy of representative structures is calculated through high-level quantum chemical calculations. GPCR-SAS This web application takes advantage of the structural similarity among GPCRs’ transmembrane regions to perform statistical analysis of sequence positions or motifs within the transmembrane helices of GPCR A, B, C, and F classes. GPCRSAS provides different types of analysis such as position/positions/range of positions conservation, entropy, co-evolutionary (co-variance) and correlation analysis. Additionally, there is the possibility of drawing a snakeplot representation with conservation information. The extracellular entrance provides selectivity to 5-HT7 receptor antagonists with antidepressant –like behavior in vivo This work highlights the importance of the low conserved extracellular part of the serotonin receptors in ligand selectivity. The binding mode of a selective 5HT7 receptor antagonist with antidepressant activity is described, opening the way for a new generation of antidepressant drugs.
Foguet, Coll Carles. "Development of model-driven approaches for metabolic flux analysis and anticancer drug discovery." Doctoral thesis, Universitat de Barcelona, 2019. http://hdl.handle.net/10803/668644.
Full textMezzanotte, Laura <1982>. "Bioanalytical applications of multicolour bioluminescence imaging: new tools for drug discovery and development." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2011. http://amsdottorato.unibo.it/3536/.
Full textChen, Jonathan Jun Feng. "Data Mining/Machine Learning Techniques for Drug Discovery: Computational and Experimental Pipeline Development." University of Akron / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=akron1524661027035591.
Full textHendry, Adam. "Xenopus laevis as a chemical genetic screening tool for drug discovery and development." Thesis, University of East Anglia, 2014. https://ueaeprints.uea.ac.uk/49595/.
Full textMyers, Samuel Harry. "Development of novel receptor tyrosine kinase inhibitors by a chemocentric approach." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28769.
Full textChee, Xavier. "Rational development of new inhibitors of lipoteichoic acid synthase." Thesis, University of Cambridge, 2017. https://www.repository.cam.ac.uk/handle/1810/269766.
Full textJoshi, Priyanka. "Targeting intrinsically disordered proteins associated with neurodegenerative diseases : a strategy towards drug discovery." Thesis, University of Cambridge, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.709234.
Full textSudwarts, Ari. "Zebra fish as a model for translational neurobiology : implications for drug discovery and development." Thesis, Queen Mary, University of London, 2017. http://qmro.qmul.ac.uk/xmlui/handle/123456789/25979.
Full textChen, Yang. "DEVELOPMENT OF COMPUTATIONAL APPROACHES FOR MEDICAL IMAGE RETRIEVAL, DISEASE GENE PREDICTION, AND DRUG DISCOVERY." Case Western Reserve University School of Graduate Studies / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1435601642.
Full textO'Rourke, Catriona. "Development of novel, robust 3D CNS tissue models for neurobiological studies and drug discovery." Thesis, Open University, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.700133.
Full textHsin, Kun-Yi. "Development and use of databases for ligand-protein interaction studies." Thesis, University of Edinburgh, 2010. http://hdl.handle.net/1842/3974.
Full textTiwana, Gaganpreet Singh. "Discovery and investigation of novel radiosensitising genes." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:ee44297c-9b01-4c31-a4f8-6be3585c3557.
Full textMehta, Kalpita Deepak. "Commercialization of Transiently Transfected Cell Lines for High Throughput Drug Screening and Profiling Applications." Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1269628794.
Full textZhang, Xudong. "3-D cell-based high-throughput screening for drug discovery and cell culture process development." Columbus, Ohio : Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1204701561.
Full textSantiago, Daniel Navarrete. "Use and Development of Computational Tools in Drug Discovery: From Small Molecules to Cyclic Peptides." Scholar Commons, 2012. http://scholarcommons.usf.edu/etd/4398.
Full textPatel, Hitesh [Verfasser], and Irmgard [Akademischer Betreuer] Merfort. "Use and development of chem-bioinformatics tools and methods for drug discovery and target identification." Freiburg : Universität, 2015. http://d-nb.info/1115495917/34.
Full textCaldwell, Colby G. "Chemical investigations of South American plants: Applications to drug discovery, biodiversity conservation and economic development." Diss., The University of Arizona, 2000. http://hdl.handle.net/10150/279829.
Full textTian, Honglei. "A high throughput screening method for anti-cancer drug leads discovery from the herbal medicine /." View abstract or full-text, 2006. http://library.ust.hk/cgi/db/thesis.pl?BIEN%202006%20TIAN.
Full textBeaudry, Francis. "Development of analytical methods based on liquid chromatography and mass spectrometry techniques to support drug discovery and development programmes." Thesis, Anglia Ruskin University, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.436459.
Full textKashif, Muhammad. "Integrated Computational and Experimental Approaches for Accelerated Drug Combination Discovery and Development : Applications in Cancer Pharmacology." Doctoral thesis, Uppsala universitet, Cancerfarmakologi och beräkningsmedicin, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-245573.
Full textMitchell, Sophie Lousie. "A fragment-based drug discovery approach for the development of selective inhibitors of protein kinase CK2." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/278650.
Full textKontijevskis, Aleksejs. "Modeling the Interaction Space of Biological Macromolecules: A Proteochemometric Approach : Applications for Drug Discovery and Development." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8916.
Full textGhiasi, Zahra. "Development of a Computational Mechanism to Generate Molecules with Drug-likeCharacteristics." Ohio University / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou162861276157897.
Full textOrtiz, València Héctor. "Contributions to the development and validation of fMRI-based biomarkers for drug discovery in social anxiety disorder." Doctoral thesis, Universitat Politècnica de Catalunya, 2016. http://hdl.handle.net/10803/440530.
Full textAquest document presenta el marc teòric I el treball experimental fet per a desenvolupar i validar un conjunt d’experiments basats en ressonància magnètica funcional (RMf). Aquests experiments estan orientats a demostrar que la RMf pot contribuir a la quantificació de la resposta al tractament de pacients amb fòbia social (FS). La RMf és una tècnica d’imatge no invasiva que proporciona indicadors d’activitat cerebral localitzats espacialment. L’anàlisi de RMf ha contribuït al recent salt en la comprensió del cervell humà. No obstant, la recerca clínica en psiquiatria encara no aprofita tot el potencial de la RMf. Al mateix temps, els costos d’avaluació de fàrmacs estan arribant a nivells inassumibles. Es fa la hipòtesi que la incorporació de RMf als assajos clínics de tractaments per a fòbia social pot proporcionar biomarcadors de resposta al tractament. Aquests biomarcadors podrien, en un futur, reduir els costos associats al desenvolupament farmacològic. En aquest document es presenten cinc estudis que formen un camí evolutiu cap a la validació de la hipòtesis. L’estudi 1 mostra un estudi pilot amb un paradigma validat a la literatura en una mostra no clínica. Les activacions identificades amb relació al paradigma estan alineades amb la literatura. No obstant, els resultats no mostren una correlació amb la severitat dels símptomes. Un anàlisi exploratori revela que la interacció de la activitat de dues àrees associades al processament emocional sí que tenen una correlació significativa amb els símptomes de fòbia social. Aquests resultats varen emfatitzar la potencial contribució als nostres objectius dels estudis basats en connectivitat funcional . L’estudi 2 explora la reproductibilitat d’anàlisis de connectivitat de RMf. Per a fer-ho, una xarxa cerebral ha estat seleccionada i explorada amb Anàlisi de Components Independents (ICA). Això s’ha realitzat amb dades capturades en tres paradigmes substancialment diferents: En repòs, en estat de dilema moral i en una tasca de Stroop d’alta demanda cognitiva. La xarxa seleccionada es va identificar sistemàticament en els tres casos, exemplificant la robustesa de la tècnica. L’estudi 3 explora la sensitivitat de ICA analitzant dades on el subjecte està en repòs abans i després d’una inducció experimental de tristesa. Múltiples regions varen mostrar canvis en la seva connectivitat intra-xarxa després de la inducció de tristesa. Els resultats es varen validar fent servir un re-anàlisi de dues meitats de la mostra i amb anàlisi de connectivitat funcional basada en un punt font (seed). Els resultats donen suport a la idea que l’anàlisi espacial de ICA no només és robust, sinó també sensible. L’estudi 4 presenta un nou paradigma de provocació de símptomes en FS que es valida en una mostra de pacients i controls. L’anàlisi d’aquesta prova pilot mostra un reveladora relació no lineal entre l’activació produïda per la tasca i l’índex de simptomatologia de fòbia social. Aquesta relació no lineal és compatible amb algunes de les inconsistències identificades a la literatura en relació a l’alteració en FS d’àrees del cervell vinculades a la regulació emocional. L’estudi 5 presenta els resultats d’un petit assaig clínic controlat per placebo que avalua, en pacients, la resposta d’un tractament d’ús habitual en FS (paroxetina). Emprant la experiència dels estudis 1 a 4, els subjectes es varen explorar executant la tasca de processament de cares emotives, la tasca de provocació de símptomes i en repòs. S’han identificat efectes del tractament en àrees vinculades al processament de por, estrès i angoixa, que s’han reportat prèviament com a alterades amb FS. És de destacar que ICA va revelar sensitivitat a millores clíniques induïdes farmacològicament en les mateixes àrees que la tasca de provocació de símptomes. En conjunció amb la recerca bibliogràfica, els mètodes i resultats obtinguts al llarg d’aquesta test proporcionen una prova de concepte en l’ús de la RMf per a la recerca clínica en FS.
Weigt, David [Verfasser], and Britta [Akademischer Betreuer] Brügger. "Development of cellular metabolite-based MALDI mass spectrometry assays for drug discovery / David Weigt ; Betreuer: Britta Brügger." Heidelberg : Universitätsbibliothek Heidelberg, 2019. http://d-nb.info/1198484314/34.
Full textAbshire, James R. (James Robbins). "Development of novel chemical biology tools to probe malaria parasite physiology and aid in antimalarial drug discovery." Thesis, Massachusetts Institute of Technology, 2015. http://hdl.handle.net/1721.1/98921.
Full textThis electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Cataloged from student-submitted PDF version of thesis.
Includes bibliographical references.
Malaria remains a major burden to global public health. Antimalarial drugs are a mainstay in efforts to control and eventually eradicate this disease. However, increasing drug resistance threatens to reverse recent gains in malaria control, making the discovery of new antimalarials critical. Antimalarial discovery is especially challenging due to the unique biology of malaria parasites, the scarcity of tools for identifying new drug targets, and the poorly understood mechanisms of action of existing antimalarials. Therefore, this work describes the development of two chemical biology tools to address unmet needs in antimalarial drug discovery. A particular challenge in antimalarial development is a shortage of validated parasite drug targets. Potent antimalarials with demonstrated clinical efficacy, like the aminoquinolines and artemisinins, represent a promising basis for rational drug development. Unfortunately, the molecular targets of these drugs have not been identified. While both are thought to interact with parasite heme, linking in vitro heme binding with drug potency remains challenging because labile heme is difficult to quantify in live cells. This work presents a novel genetically-encoded heme biosensor and describes its application to quantify labile heme in live malaria parasites and test mechanisms of antimalarial action. Another challenge is posed by the widespread malaria parasite Plasmodium vivax, which, unlike P. falciparum, cannot be propagated in vitro, hindering research into parasite biology and drug target identification. P. vivax preferentially invades reticulocytes, which are impractical to obtain in continuous supply. The basis for this invasion tropism remains incompletely understood, mainly because current tools cannot directly link molecular binding events to invasion outcomes. This work presents novel methods for immobilizing synthetic receptors on the red blood cell surface. These receptors are used in proof-of-concept experiments to investigate requirements for efficient invasion via a well-characterized P. falciparum invasion pathway, suggesting this method can be used to elucidate molecular mechanisms underlying parasite invasion tropisms. Future receptor designs could promote the invasion of P. vivax into mature red blood cells and potentially facilitate practical in vitro culture. Taken together, these tools present new opportunities for drug discovery to aid efforts in malaria control and eventual eradication.
by James R. Abshire.
Ph. D.
Fraser, Craig. "Design and development of novel mTOR and SRC family kinase inhibitors via a phenotypic drug discovery approach." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/21689.
Full textFienberg, Stephen. "Development of N-domain selective Angiotensin-I Converting Enzyme (ACE) inhibitors using Computer Aided Drug Discovery (CADD)." Doctoral thesis, University of Cape Town, 2017. http://hdl.handle.net/11427/25656.
Full textShuman, Cynthia F. "Interaction Characteristics of Viral Protease Targets and Inhibitors : Perspectives for drug discovery and development of model systems." Doctoral thesis, Uppsala universitet, Institutionen för naturvetenskaplig biokemi, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3342.
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