Relevant bibliographies by topics / Master of Drug Discovery and Development

Academic literature on the topic 'Master of Drug Discovery and Development'

Author: Grafiati
Published: 10 December 2022
Last updated: 28 January 2023

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Journal articles on the topic "Master of Drug Discovery and Development"

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Yu, Bingting, Ruslan Mamedov, Gwenny M. Fuhler, and Maikel P. Peppelenbosch. "Drug Discovery in Liver Disease Using Kinome Profiling." International Journal of Molecular Sciences 22, no. 5 (March 5, 2021): 2623. http://dx.doi.org/10.3390/ijms22052623.

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The liver is one of the most important organs, playing critical roles in maintaining biochemical homeostasis. Accordingly, disease of the liver is often debilitating and responsible for untold human misery. As biochemical nexus, with kinases being master regulators of cellular biochemistry, targeting kinase enzymes is an obvious avenue for treating liver disease. Development of such therapy, however, is hampered by the technical difficulty of obtaining comprehensive insight into hepatic kinase activity, a problem further compounded by the often unique aspects of hepatic kinase activities, which makes extrapolations from other systems difficult. This consideration prompted us to review the current state of the art with respect to kinome profiling approaches towards the hepatic kinome. We observe that currently four different approaches are available, all showing significant promise. Hence we postulate that insight into the hepatic kinome will quickly increase, leading to rational kinase-targeted therapy for different liver diseases.
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Martínez, Antón Leandro, José Brea, Marián Castro, Ángel García, Eduardo Santamaría, Óscar Lestón, and María Isabel Loza. "An Experience of Using a Canvas-Based Template for Blended-Learning in a Master in Drug Discovery." International Journal of Emerging Technologies in Learning (iJET) 17, no. 06 (March 29, 2022): 257–67. http://dx.doi.org/10.3991/ijet.v17i06.28149.

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Drug development is a complex process that requires multidisciplinary teamwork to overcome the uncertainty associated to the process. From this point, problem-based learning (PBL) methodologies are helpful to train future professionals dedicated to drug development in multidisciplinary environments. One of the strategies developed to design novel business models is Business Model Canvas (BMC), a strategy that has been widely employed in business schools, but not in scientific education. Thus, we wanted to verify if a BMC-like template was suitable for a PBL experience in the field of drug development using a blended-learning approach. The students of a research master subject were asked to create a joint project plan for the development of a novel drug for an unmet clinical need by making use of a BMC-like template as support for discussions on the project strategy, while combining online and face-to-face sessions. The methodology helped the students to learn about drug development, even in a blended-learning format. Most students considered that this methodology enhanced their participation in the working group and helped them to focus their arguments, proving that the employment of BMC-like templates is helpful to overcome the disadvantages of PBL experiences.
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Gusev, K. A., O. A. Terenteva, D. N. Maimistov, Yu E. Generalova, K. O. Sidorov, and E. V. Flisyuk. "Development of Suppositories Silicone Molds Using Additive Technologies." Drug development & registration 11, no. 4 (November 27, 2022): 116–24. http://dx.doi.org/10.33380/2305-2066-2022-11-4-116-124.

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Introduction. In modern practice, suppositories are prepared by hand rolling method or fusion. 3D printing can overcome the disadvantages of traditional suppository manufacturing methods and solve the problems of personalization. 3D printing makes it possible to manufacture drug-loaded suppositories without the use of molds or other physical support. The current studies have a number of limitations, and the printing of one suppository requires a long time. This report proposes a method of 3D modeling and 3D printing to produce personalized suppositories by fusion.Aim. Various sizes and shapes suppositories silicone molds development by molding method from hydrophilic, lipophilic and amphiphilic bases.Materials and methods. Suppository bases: cocoa butter (Luker, Colombia), polyethylene glycol (PEG) 1500 (Merck KGaA, Germany), PEG-400 (Merck KGaA, Germany), Witepsol H-15 (Chimmed Group, Russia); pharmaceutical substance: paracetamol (Hebei Jiheng (Group) Pharmaceutical Co. Ltd, China); filaments for 3D printing: polyethylene terephthalate (PET-G natural, LLC "PrintProdakt", Russia); silicone two-component platinum, hardness Shore 30A (China); solvents: Acetonitrile Grade HPLC (Merck KGaA, Germany). The design of the both casting and master molds of suppositories was carried out using the KOMPAS-3D version 17.1. Master molds were printed by Picaso PRO 250 and Picaso X Pro 3D printers. Mold segments were obtained by filling master molds with a mixture of two-component silicone. Suppositories were obtained by molding method. Their average weight and standard deviation were determined. Paracetamol concentration in suppositories was carried out by UV spectrophotometry on a UV-1240 mini spectrophotometer (Shimadzu, Япония). Silicone molds were soaked and washed in hot water with surfactants. Washouts from the molds were taken by soaking the mold.Results and discussion. The torpedo-shaped form was chosen as the model form of suppositories. For the chosen form, three volumes of suppositories were designed: 3.32 ml; 1.5 ml and 0.25 ml. Silicone molds were designed and manufactured for all volumes. The cast suppositories were examined for compliance with the regulatory documentation for the dosage form, the average weight and mass uniformity were evaluated. Suppositories with paracetamol were made. A procedure for cleaning the obtained silicone molds has been developed.Conclusion. The resulting silicone molds make it possible to obtain suppositories in accordance with the regulatory documentation for the suppositories. Silicone molds have significant advantages compared to analogues of metal or polymeric molds.
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Zheng, Hailin, Mati Fridkin, and Moussa Youdim. "New Approaches to Treating Alzheimer's Disease." Perspectives in Medicinal Chemistry 7 (January 2015): PMC.S13210. http://dx.doi.org/10.4137/pmc.s13210.

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To date, no truly efficacious drugs for Alzheimer's disease (AD) have been developed; moreover, all new anti-AD drugs developed since 2003 have failed. To succeed where previous ones have failed in drug development, new approaches for AD therapy are needed. Here we discuss the potential application of network medicine as a new approach to AD treatment. Unlike traditional approaches focused on a single target/pathway, network medicine targets and restores disease-disrupted networks through simultaneous modulation of numerous proteins (targets)/pathways involved in AD pathogenesis. We consider several drug candidates under development for AD therapy, including Keap1–Nrf2 regulators, endogenous neurogenic agents, and hypoxia-inducible factor 1 (HIF-1) activators. These drug candidates are multi-target ligands with the potential to further develop as network medicines, since they act as master regulators to initiate a broad range of cellular defense mechanisms/cytoprotective genes that exert their efficacy in a holistic way. We also explore their diverse mechanisms of action and potential disease-modifying effects, which may have profound implications for drug discovery.
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Kaizer, Alexander M., Joseph S. Koopmeiners, Michael J. Kane, Satrajit Roychoudhury, David S. Hong, and Brian P. Hobbs. "Basket Designs: Statistical Considerations for Oncology Trials." JCO Precision Oncology, no. 3 (December 2019): 1–9. http://dx.doi.org/10.1200/po.19.00194.

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Progress in the areas of genomics, disease pathways, and drug discovery has advanced into clinical and translational cancer research. The latest innovations in clinical trials have followed with master protocols, which are defined by inclusive eligibility criteria and devised to interrogate multiple therapies for a given tumor histology and/or multiple histologies for a given therapy under one protocol. The use of master protocols for oncology has become more common with the desire to improve the efficiency of clinical research and accelerate overall drug development. Basket trials have been devised to ascertain the extent to which a treatment strategy offers benefit to various patient subpopulations defined by a common molecular target. Conventionally conducted within the phase II setting, basket designs have become popular as drug developers seek to effectively evaluate and identify preliminary efficacy signals among clinical indications identified as promising in preclinical study. This article reviews basket trial designs in oncology settings and discusses several issues that arise with their design and analysis.
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Shirakawa, Tomohiko, Takashi Toyono, Asako Inoue, Takuma Matsubara, Tatsuo Kawamoto, and Shoichiro Kokabu. "Factors Regulating or Regulated by Myogenic Regulatory Factors in Skeletal Muscle Stem Cells." Cells 11, no. 9 (April 29, 2022): 1493. http://dx.doi.org/10.3390/cells11091493.

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MyoD, Myf5, myogenin, and MRF4 (also known as Myf6 or herculin) are myogenic regulatory factors (MRFs). MRFs are regarded as master transcription factors that are upregulated during myogenesis and influence stem cells to differentiate into myogenic lineage cells. In this review, we summarize MRFs, their regulatory factors, such as TLE3, NF-κB, and MRF target genes, including non-myogenic genes such as taste receptors. Understanding the function of MRFs and the physiology or pathology of satellite cells will contribute to the development of cell therapy and drug discovery for muscle-related diseases.
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Buxton, Meredith Becker, Brian Michael Alexander, Donald A. Berry, Webster K. Cavenee, Howard Colman, John Frederick De Groot, Benjamin M. Ellingson, et al. "GBM AGILE: A global, phase II/III adaptive platform trial to evaluate multiple regimens in newly diagnosed and recurrent glioblastoma." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): TPS2579. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.tps2579.

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TPS2579 Background: Glioblastoma (GBM) is an aggressive brain tumor with few effective therapies and is invariably fatal. Developing new therapies for patients with GBM requires focused interaction between industry, academia, nonprofits, patient advocacy, and health authorities, and novel approaches to clinical trials. Industry is wary of developing drugs for GBM due to the high failure rate and high cost of drug development. GBM Adaptive Global Innovative Learning Environment (GBM AGILE) Trial was designed by over 130 global key opinion leaders in consultation with health authorities to provide an optimal mechanism for phase II/III development in GBM. The Sponsor of GBM AGILE is the Global Coalition for Adaptive Research (GCAR), a non-profit organization. GCAR’s mission is to speed the discovery and development of treatments for patients with rare and deadly diseases by serving as sponsor of innovative trials. Methods: GBM AGILE is an international, seamless phase II/III platform trial designed to evaluate multiple therapies in newly diagnosed and recurrent GBM. Its goals are to identify effective therapies for GBM and match effective therapies with patient subtypes, with data generated to support regulatory filing for new drug applications. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to investigational arms based on their performance. The primary endpoint is overall survival. The trial is being conducted under a master Investigational New Drug Application/Clinical Trial Agreement and Master Protocol, allowing multiple drugs/drug combinations from different pharmaceutical companies to be evaluated simultaneously and/or over time. The plan is to add experimental therapies as new information is identified and remove therapies as they complete their individual evaluation against a common control. GBM AGILE received IND approval from the FDA in April 2019, enrolling its first patient in June 2019. Site activation is ongoing in the US, with approximately 40 US planned. The trial received CTA approval from Health Canada in January 2020. Expansion to Europe, China, and Australia is also underway. Clinical trial information: NCT03970447 .
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Chen, Po-Ling, Tsai-Teng Tzeng, Alan Yung-Chih Hu, Lily Hui-Ching Wang, and Min-Shi Lee. "Development and Evaluation of Vero Cell-Derived Master Donor Viruses for Influenza Pandemic Preparedness." Vaccines 8, no. 4 (October 25, 2020): 626. http://dx.doi.org/10.3390/vaccines8040626.

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The embryonated egg-based platform currently produces the majority of seasonal influenza vaccines by employing a well-developed master donor virus (MDV, A/PR/8/34 (PR8)) to generate high-growth reassortants (HGRs) for A/H1N1 and A/H3N2 subtypes. Although the egg-based platform can supply enough seasonal influenza vaccines, it cannot meet surging demands during influenza pandemics. Therefore, multi-purpose platforms are desirable for pandemic preparedness. The Vero cell-based production platform is widely used for human vaccines and could be a potential multi-purpose platform for pandemic influenza vaccines. However, many wild-type and egg-derived influenza viruses cannot grow efficiently in Vero cells. Therefore, it is critical to develop Vero cell-derived high-growth MDVs for pandemic preparedness. In this study, we evaluated two in-house MDVs (Vero-15 and VB5) and two external MDVs (PR8 and PR8-HY) to generate Vero cell-derived HGRs for five avian influenza viruses (AIVs) with pandemic potentials (H5N1 clade 2.3.4, H5N1 clade 2.3.2.1, American-lineage H5N2, H7N9 first wave and H7N9 fifth wave). Overall, no single MDV could generate HGRs for all five AIVs, but this goal could be achieved by employing two in-house MDVs (vB5 and Vero-15). In immunization studies, mice received two doses of Vero cell-derived inactivated H5N1 and H7N9 whole virus antigens adjuvanted with alum and developed robust antibody responses.
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Chavan, Sandeep, Sonali Tayade, Vidya Gupta, Vineeta Deshmukh, and Sadanand Sardeshmukh. "Pharmaceutical Standardization and Physicochemical Characterization of Traditional Ayurvedic Marine Drug: Incinerated Conch Shell (Shankha Bhasma)." Marine Drugs 16, no. 11 (November 15, 2018): 450. http://dx.doi.org/10.3390/md16110450.

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Natural resources such as plants, animals and minerals have always been used by mankind to develop drugs and marine world is no exception. Marine by-products like conches, pearls, mother of pearl shells, corals and so forth have been used by traditional Ayurvedic practitioners for centuries. The unique methods of these preparations are scientifically designed to eliminate unwanted impurities and convert them into bioavailable form. In this study, Conch (Xanchus pyrum) was used as a marine resource of calcium carbonate and was converted pharmaceutically from its aragonite form to calcite. All the steps of preparations and changes in the properties therein were documented and validated. Further, traditional as well as modern analytical tools were used to study its physical and chemical characters to develop a monograph. The physical characterization included particle size, X-ray diffraction (XRD), Scanning Electron Microscopy (SEM), Thermogravimetric Analysis (TGA) and Fourier Transform Infra-red (FTIR). Metal composition and heavy metal limits were determined using Inductively Coupled Plasma Optical Emission Spectrometry (ICPOES). This study revealed the rearrangement of aragonite crystals into calcite form by grinding, trituration with aloe vera juice and incineration under controlled conditions. Moreover, the finished product was found to be devoid of organic matrix that is nacre. This study creates a foundation for the development of a master formula for commonly used Shankha Bhasma in Ayurvedic medicines.
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Wu, Guoyu, Junyang Yi, Ling Liu, Pengcheng Wang, Zhijie Zhang, and Zhen Li. "Pseudoginsenoside F11, a Novel Partial PPARγAgonist, Promotes Adiponectin Oligomerization and Secretion in 3T3-L1 Adipocytes." PPAR Research 2013 (2013): 1–8. http://dx.doi.org/10.1155/2013/701017.

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PPARγis a nuclear hormone receptor that functions as a master regulator of adipocyte differentiation and development. Full PPARγagonists, such as the thiazolidinediones (TZDs), have been widely used to treat type 2 diabetes. However, they are characterized by undesirable side effects due to their strong agonist activities. Pseudoginsenoside F11 (p-F11) is an ocotillol-type ginsenoside isolated fromPanax quinquefolium L.(American ginseng). In this study, we found that p-F11 activates PPARγwith modest adipogenic activity. In addition, p-F11 promotes adiponectin oligomerization and secretion in 3T3-L1 adipocytes. We also found that p-F11 inhibits obesity-linked phosphorylation of PPARγat Ser-273 by Cdk5. Therefore, p-F11 is a novel partial PPARγagonist, which might have the potential to be developed as a new PPARγ-targeted therapeutics for type 2 diabetes.
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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.

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Gage, Zoe O. "Interferon, viruses and drug discovery." Thesis, University of St Andrews, 2017. http://hdl.handle.net/10023/10127.

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The interferon (IFN) response is a crucial component of cellular innate immunity, vital for controlling virus infections. Dysregulation of the IFN response however can lead to serious medical conditions including autoimmune disorders. Modulators of IFN induction and signalling could be used to treat these diseases and as tools to further understand the IFN response and viral infections. We have developed cell-based assays to identify modulators of IFN induction and signalling, based on A549 cell lines where a GFP gene is under the control of the IFN-β promoter (A549/pr(IFN-β).GFP) and the ISRE containing MxA promoter (A549/pr(ISRE).GFP) respectively. The assays were optimized, miniaturized and validated as suitable for HTS by achieving Z' Factor scores >0.6. A diversity screen of 15,667 compounds using the IFN induction reporter assay identified 2 hit compounds (StA-IFN-1 and StA-IFN-4) that were validated as specifically inhibiting IFNβ induction. Characterisation of these molecules demonstrated that StA-IFN-4 potently acts at, or upstream, of IRF3 phosphorylation. We successfully expanded this HTS platform to target viral interferon antagonists acting upon IFN-signalling. An additional assay was developed where the A549/pr(ISRE).GFP.RBV-P reporter cell line constitutively expresses the Rabies virus phosphoprotein. A compound inhibiting viral protein function will restore GFP expression. The assay was successfully optimized for HTS and used in an in-house screen. We further expanded this assay by placing the expression of RBV-P under the control of an inducible promoter. This demonstrates a convenient approach for assay development and potentiates the targeting of a variety of viral IFN antagonists for the identification of compounds with the potential to develop a novel class of antiviral drugs.
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Cereto, Massagué Adrià. "Development of tools for in silico drug discovery." Doctoral thesis, Universitat Rovira i Virgili, 2017. http://hdl.handle.net/10803/454678.

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El cribratge virtual és un mètode quimioinformàtic que consisteix en cribrar molècules bioactives de grans bases de dades de molècules petites. Això permet als investigadors d’estalviar-se el cost de provar experimentalment cents o milers de compostos candidats, reduïnt-ne el nombre fins a quantitats manejables. Per a la validació dels mètodes de cribratge virtual calen biblioteques de molècules cimbell. El programari DecoyFinder fou desenvolupat com a aplicació gràfica de fàcil ús per a la construcció de biblioteques de molècules cimbell, i fou posteriorment ampliat amb les troballes de recerca posterior sobre la construcció i rendiment de biblioteques de molècules cimbell. El Protein Data Bank (PDB) és molt útil perquè proporciona estructures tridimensionals per a complexos proteïna-lligand, i per tant, informació sobre com interactuen. Pels mètodes de cribratge virtual que en depenen, n’és extremadament important la seva fiabilitat. El VHELIBS fou desenvolupat com a eina per a inspeccionar i identificar, fàcilment i intuitiva, les estructures fiables del PDB, basant-se en com de bo n’és l’encaix amb els seus corresponents mapes de densitat electrònica. Mentre que el cribratge virtual prova de trobar noves molècules bioactives per determinades dianes, l’enfoc invers també s’empra: arran d’una molècula, cercar-ne dianes amb activitat biològica no documentada. Aquest cribratge invers és conegut en anglès com a “in silico target fishing”, o pesca de dianes “in silico”, i és especialment útil a l’àmbit de la reutilització de fàrmacs En començar aquesta tesi, no hi havia cap plataforma de “target fishing” de lliure accés, i tot i que durant els anys se n’han desenvolupat algunes, en tots els casos la seva predicció de bioactivitat és qualitativa. Per això es desenvolupà una plataforma pròpia de “target fishing” de lliure accés, amb la implementació d’un nou mètode que proporciona la primera predicció quantitativa de bioactivitat per aquest tipus de plataforma.
El 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.
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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.

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Computational drug design methods have become increasingly invaluable in the drug discovery and development process. Throughout this thesis will be described the development and application of methods that are used at every stage of the drug discovery and development pipeline. In Chapter 2 will take a look at the use computational methods towards the understanding and development of two novel Bcl-2 inhibitors, Obatoclax and ABT-737, being developed for the treatment of Cancer. The study proposes certain mechanisms through which ABT-737 displays selectivity towards certain targets within the Bcl-2 family. Additionally, we propose a binding mode for Obatoclax which is in accordance with experimental data. The following Chapter addresses the use of virtual screening for the identification of novel lead compounds. Trypanosoma brucei RNA Editing Ligase 1 was chosen as the target for the development of treatments against Trypanosoma infections and C35, a potent novel inhibitor of the enzyme, was identified. Furthermore, our research shows that the action of C35 extends to inhibition of several critical enzyme activities required for the RNA editing process as well as compromising the integrity of the multiprotein complex which carries it out. The following Chapter takes a look at the use of mass spectrometry data in order to expedite discovery of bioactive compounds in natural products. We developed an algorithm which analyses MS/MS data in order to derive the Molecular Formula of the compound. The novel algorithm obtained a 95% success rate on a test set of 91 compounds. The last Chapter of the thesis explores the use of molecular dynamics to generate a conformational ensemble of targets for virtual screening. Conformational ensembles were generated for a target test set taken from the Directory for Useful Decoys. The results showed that molecular dynamics-based conformational ensembles provided remarkable improvements on 2 of the targets tested due to the enhanced capacity to properly dock compounds in otherwise restricted structures. The last Chapter of the thesis is a general discussion on the work of the thesis and a proposal on how all can be integrated within the drug discovery and development pipeline.
Les 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.
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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.

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Molecular and Cellular Physiology
Ph.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
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Schreiber, Kimberly C. M. "Assay development for use in drug discovery against Bovine Trichomoniasis." Scholarly Commons, 2007. https://scholarlycommons.pacific.edu/uop_etds/650.

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Bovine trichomoniasis is a venereal disease that affects cattle. The causative agent of this disease is Tritrichomonas foetus, a flagellated protozoan. There is no current FDA approved treatment for this disease. The purpose of this study was to develop new compound screening assays that will make the discovery of new compounds faster and more accurate. The CellTiter-Glo Luminescent Cell Viability Assay, a high throughput screening (HTS) assay from Promega, was found to be as affective at measuring cytotoxicity as traditional assaying techniques. For the first time. preen florescent protein. a reporter gene used in cell viability assavs was successfully transformed into T. foetus for use in HTS systems. This study also identified new compounds that can potentially be used as new treatments for this disease.
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Miller, 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.

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Fibrotic diseases can be attributed to approximately 45% of deaths within western developed countries. This category of disease can affect nearly every tissue in the body, predominantly liver, kidney, and lung. The severity of fibrotic diseases is widely recognised but currently there is no accepted effective disease modifying treatment. There have been a number of potential drug targets identified in recent years, including the enzyme autotaxin (ATX) and the RGD integrins, which are known to play a key role in the pathogenesis. In collaboration with GlaxoSmithKline, the projects detailed in this report were aimed to develop small molecule inhibitors with drug like physicochemical properties for fibrosis drug discovery. Chapter 1 focusses on the secreted enzyme ATX, which is responsible for the hydrolysis of lysophosphatidylcholine (LPC) to the bioactive lysophosphatidic acid (LPA) and choline. The ATX-LPA signalling pathway is implicated in cell survival, migration, and proliferation; thus, the inhibition of ATX is a recognised therapeutic target for a number of diseases including fibrotic diseases, cancer, and inflammation, amongst others. Many of the developed synthetic inhibitors for ATX have resembled the lipid chemotype of the native ligand; however, a small number of inhibitors have been described that deviate from this common scaffold. Herein, Chapter 1 details the structure-activity relationship (SAR) exploration of a previously reported small molecule ATX inhibitor through the design, synthesis, and biological evaluation of aseries of analogues. Furthermore, using enzyme kinetics studies it is shown that analogues of this chemotype are noncompetitive inhibitors, and using a crystal structure with ATX the discrete binding mode was confirmed. This work has provided valuable insight into the binding of this chemotype, which could aid the design of novel ATX inhibitors with non-lipid-like scaffolds. Chapter 2 describes a lead-optimisation project targeting the RGD subfamily of the integrin receptors. The RGD integrins are recognised therapeutic targets for thrombosis, fibrosis, and cancer, amongst others. Current inhibitors are designed to mimic the tripeptide sequence of the natural ligands (arginine-glycine-aspartic acid); however, the RGD-mimetic antagonists for one particular RGD integrin (αIIbβ3) have been shown to cause partial agonism, leading to the opposite pharmacological effect. The challenge of obtaining oral activity and synthetic tractability with RGD-mimetic molecules, along with the issues relating to pharmacology, has left integrintherapeutics in need of a new strategy. Recently, a new generation of inhibitor has emerged that lacks the RGD-mimetic. The work detailed herein aimed to build on this emerging area, with the design, synthesis, and biological evaluation of novel small molecule inhibitors targeting the αvβ3 integrin. These compounds are shown to be accessed via synthetically divergent routes, allowing for the quick exploration of adiverse set of potential lead compounds. Initial efforts led to the identification offour promising lead-like inhibitors with pIC50 values ranging from 4.1-5.5 for the target integrin αvβ3. Unfortunately, the initial hit compound, that the subsequent compound design stemmed from, was later determined to be a false positive, and as a result work on the project ceased. Thus, Chapter 2 details a project that was misled due to false positive assay results.
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Hatherley, Rowan. "Structural bioinformatics studies and tool development related to drug discovery." Thesis, Rhodes University, 2016. http://hdl.handle.net/10962/d1020021.

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This thesis is divided into two distinct sections which can be combined under the broad umbrella of structural bioinformatics studies related to drug discovery. The first section involves the establishment of an online South African natural products database. Natural products (NPs) are chemical entities synthesised in nature and are unrivalled in their structural complexity, chemical diversity, and biological specificity, which has long made them crucial to the drug discovery process. South Africa is rich in both plant and marine biodiversity and a great deal of research has gone into isolating compounds from organisms found in this country. However, there is no official database containing this information, making it difficult to access for research purposes. This information was extracted manually from literature to create a database of South African natural products. In order to make the information accessible to the general research community, a website, named “SANCDB”, was built to enable compounds to be quickly and easily searched for and downloaded in a number of different chemical formats. The content of the database was assessed and compared to other established natural product databases. Currently, SANCDB is the only database of natural products in Africa with an online interface. The second section of the thesis was aimed at performing structural characterisation of proteins with the potential to be targeted for antimalarial drug therapy. This looked specifically at 1) The interactions between an exported heat shock protein (Hsp) from Plasmodium falciparum (P. falciparum), PfHsp70-x and various host and exported parasite J proteins, as well as 2) The interface between PfHsp90 and the heat shock organising protein (PfHop). The PfHsp70-x:J protein study provided additional insight into how these two proteins potentially interact. Analysis of the PfHsp90:PfHop also provided a structural insight into the interaction interface between these two proteins and identified residues that could be targeted due to their contribution to the stability of the Hsp90:Hop binding complex and differences between parasite and human proteins. These studies inspired the development of a homology modelling tool, which can be used to assist researchers with homology modelling, while providing them with step-by-step control over the entire process. This thesis presents the establishment of a South African NP database and the development of a homology modelling tool, inspired by protein structural studies. When combined, these two applications have the potential to contribute greatly towards in silico drug discovery research.
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Yamaura, 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.

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Pilger, 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.

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Books on the topic "Master of Drug Discovery and Development"

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Dikshit, Madhu, ed. Drug Discovery and Drug Development. Singapore: Springer Singapore, 2021. http://dx.doi.org/10.1007/978-981-15-8002-4.

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Rang, H. P., and Raymond Hill. Drug discovery and development. 2nd ed. Edinburgh: Elsevier, 2012.

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Drug discovery and development. 2nd ed. Edinburgh: Elsevier, 2012.

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Chorghade, Mukund S., ed. Drug Discovery and Development. Hoboken, NJ, USA: John Wiley & Sons, Inc., 2006. http://dx.doi.org/10.1002/0471780103.

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O’Donnell III, James J., John Somberg, Vincent Idemyor, and James T. O’Donnell, eds. Drug Discovery and Development. Third edition. | Boca Raton, Florida : CRC Press, 2019. |: CRC Press, 2019. http://dx.doi.org/10.1201/9781315113470.

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Chorghade, Mukund S., ed. Drug Discovery and Development. Hoboken, NJ, USA: John Wiley & Sons, Inc., 2006. http://dx.doi.org/10.1002/0470085223.

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Williams, Michael, and Jeffrey B. Malick, eds. Drug Discovery and Development. Totowa, NJ: Humana Press, 1987. http://dx.doi.org/10.1007/978-1-4612-4828-6.

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Poduri, Ramarao, ed. Drug Discovery and Development. Singapore: Springer Singapore, 2021. http://dx.doi.org/10.1007/978-981-15-5534-3.

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S, Chorghade Mukund, ed. Drug discovery and development. Hoboken, N.J: Wiley, 2006.

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Liu, Xinyong, Peng Zhan, Luis Menéndez-Arias, and Vasanthanathan Poongavanam, eds. Antiviral Drug Discovery and Development. Singapore: Springer Singapore, 2021. http://dx.doi.org/10.1007/978-981-16-0267-2.

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Book chapters on the topic "Master of Drug Discovery and Development"

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Turner, J. Rick. "Drug Discovery." In New Drug Development, 21–34. New York, NY: Springer New York, 2010. http://dx.doi.org/10.1007/978-1-4419-6418-2_3.

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Washburn, William N. "Chapter 3. SGLT2 Inhibitors in Development." In Drug Discovery, 29–87. Cambridge: Royal Society of Chemistry, 2012. http://dx.doi.org/10.1039/9781849735322-00029.

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Filipski, Kevin J., Benjamin D. Stevens, and Jeffrey A. Pfefferkorn*. "Chapter 4. Glucokinase Activators in Development." In Drug Discovery, 88–108. Cambridge: Royal Society of Chemistry, 2012. http://dx.doi.org/10.1039/9781849735322-00088.

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Macchiarulo, Antonio, Antimo Gioiello, and Roberto Pellicciari*. "Chapter 10. TGR5 Agonists in Development." In Drug Discovery, 270–305. Cambridge: Royal Society of Chemistry, 2012. http://dx.doi.org/10.1039/9781849735322-00270.

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Perni, Robert B., Vipin Suri, Thomas V. Riera, Joseph Wu, Charles A. Blum, George P. Vlasuk, and James L. Ellis*. "Chapter 13. SIRT1 Activators in Development." In Drug Discovery, 366–402. Cambridge: Royal Society of Chemistry, 2012. http://dx.doi.org/10.1039/9781849735322-00366.

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Bourbeau, Matthew P. "Chapter 16. ACC Inhibitors in Development." In Drug Discovery, 464–500. Cambridge: Royal Society of Chemistry, 2012. http://dx.doi.org/10.1039/9781849735322-00464.

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Demong*, Duane E., and M. W. Miller. "Chapter 15. Glucagon Receptor Antagonists in Development." In Drug Discovery, 429–63. Cambridge: Royal Society of Chemistry, 2012. http://dx.doi.org/10.1039/9781849735322-00429.

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Ying, Weiwen. "CHAPTER 6. Discovery and Development of Ganetespib." In Drug Discovery, 180–97. Cambridge: Royal Society of Chemistry, 2013. http://dx.doi.org/10.1039/9781849739689-00180.

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Mitscher, Lester A., and Apurba Dutta. "Contemporary Drug Discovery." In Drug Discovery and Development, 103–28. Hoboken, NJ, USA: John Wiley & Sons, Inc., 2006. http://dx.doi.org/10.1002/0471780103.ch3.

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Solon, Eric G. "Chapter 6. Autoradiography in Pharmaceutical Discovery and Development." In Drug Discovery, 309–42. Cambridge: Royal Society of Chemistry, 2011. http://dx.doi.org/10.1039/9781849732918-00309.

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Conference papers on the topic "Master of Drug Discovery and Development"

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Miftahof, R., and N. Akhmadeev. "Mathematical modeling in drug discovery and development." In BIOMED 2007. Southampton, UK: WIT Press, 2007. http://dx.doi.org/10.2495/bio070301.

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Sathiaseelan, Allimalar, Chong Seng Shit, and Tsun-Thai Chai. "ANTI-BIOFILM ACTIVITY OF FERMENTED SOYBEAN TEMPEH EXTRACTS AND FRACTIONS AGAINST ORAL PRIMARY COLONIZER BACTERIA." In International Conference on Drug Discovery & Development. The International Institute of Knowledge Management (TIIKM), 2018. http://dx.doi.org/10.17501/icddd.2017.1101.

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Ransom, John T., Bruce S. Edwards, Frederick W. Kuckuck III, Alex Okun, David K. Mattox, Eric R. Prossnitz, and Larry A. Sklar. "Flow cytometry systems for drug discovery and development." In BiOS 2000 The International Symposium on Biomedical Optics, edited by Daniel L. Farkas and Robert C. Leif. SPIE, 2000. http://dx.doi.org/10.1117/12.384201.

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Ibáñez Antolín, Ane. "Applications of Machine Learning in drug discovery and development." In MOL2NET'21, Conference on Molecular, Biomedical & Computational Sciences and Engineering, 7th ed. Basel, Switzerland: MDPI, 2021. http://dx.doi.org/10.3390/mol2net-07-11234.

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Bednar, Bohumil. "Development of Optical Imaging Biomarkers and Applications in Drug Discovery and Development." In Biomedical Optics. Washington, D.C.: OSA, 2010. http://dx.doi.org/10.1364/biomed.2010.bma2.

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Momtahen, Shadi, Furat Al-Obaidy, and Farah Mohammadi. "Machine Learning with Digital Microfluidics for Drug Discovery and Development." In 2019 IEEE Canadian Conference of Electrical and Computer Engineering (CCECE). IEEE, 2019. http://dx.doi.org/10.1109/ccece.2019.8861842.

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Kumazawa, Shigenori. "Bioactive compounds in bee propolis for drug discovery." In 2ND BIOMEDICAL ENGINEERING’S RECENT PROGRESS IN BIOMATERIALS, DRUGS DEVELOPMENT, AND MEDICAL DEVICES: Proceedings of the International Symposium of Biomedical Engineering (ISBE) 2017. Author(s), 2018. http://dx.doi.org/10.1063/1.5023948.

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Khalil, Iya. "Abstract SY14-03: Inferring causality for oncology drug discovery and development." In Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-sy14-03.

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Chandra, Rini, Mohammed Javed, Bulla Rajesh, B. S. Sanjeev, and Shahnawaz Khijmatgar. "Target-less Drug Discovery Pipeline using Feature Driven Development (FDD) model." In 2021 IEEE International Conference on Bioinformatics and Biomedicine (BIBM). IEEE, 2021. http://dx.doi.org/10.1109/bibm52615.2021.9669585.

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Hait, William N. "Abstract IA-12: Oncology drug discovery and development in the 21st century." In Abstracts: First AACR International Conference on Frontiers in Basic Cancer Research--Oct 8–11, 2009; Boston MA. American Association for Cancer Research, 2009. http://dx.doi.org/10.1158/0008-5472.fbcr09-ia-12.

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Reports on the topic "Master of Drug Discovery and Development"

1

Wirth, Dyann F. New Strategies for Drug Discovery and Development for Plasmodium Falciparum. Fort Belvoir, VA: Defense Technical Information Center, January 2000. http://dx.doi.org/10.21236/ada375802.

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Wang, Yanming. InVivo Imaging of Myelination for Drug Discovery and Development in Multiple Sclerosis. Fort Belvoir, VA: Defense Technical Information Center, October 2012. http://dx.doi.org/10.21236/ada580016.

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Efange, Simon, and Deborah C. Mash. Drug Development and Conservation of Biodiversity in West and Central Africa: Performance of Neurochemical and Radio Receptor Assays of Plant Extracts Drug Discovery for the Central Nervous System. Fort Belvoir, VA: Defense Technical Information Center, September 2004. http://dx.doi.org/10.21236/ada474867.

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Jarron, Matthew, Amy R. Cameron, and James Gemmill. Dundee Discoveries Past and Present. University of Dundee, November 2020. http://dx.doi.org/10.20933/100001182.

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A series of self-guided walking tours through pioneering scientific research in medicine, biology, forensics, nursing and dentistry from the past to the present. Dundee is now celebrated internationally for its pioneering work in medical sciences, in particular the University of Dundee’s ground-breaking research into cancer, diabetes, drug development and surgical techniques. But the city has many more amazing stories of innovation and discovery in medicine and biology, past and present, and the three walking tours presented here will introduce you to some of the most extraordinary. Basic information about each topic is presented on this map, but you will ­find more in-depth information, images and videos on the accompanying website at uod.ac.uk/DundeeDiscoveriesMap For younger explorers, we have also included a Scavenger Hunt – look out for the cancer cell symbols on the map and see if you can ­find the various features listed along the way!
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Cytryn, Eddie, Mark R. Liles, and Omer Frenkel. Mining multidrug-resistant desert soil bacteria for biocontrol activity and biologically-active compounds. United States Department of Agriculture, January 2014. http://dx.doi.org/10.32747/2014.7598174.bard.

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Control of agro-associated pathogens is becoming increasingly difficult due to increased resistance and mounting restrictions on chemical pesticides and antibiotics. Likewise, in veterinary and human environments, there is increasing resistance of pathogens to currently available antibiotics requiring discovery of novel antibiotic compounds. These drawbacks necessitate discovery and application of microorganisms that can be used as biocontrol agents (BCAs) and the isolation of novel biologically-active compounds. This highly-synergistic one year project implemented an innovative pipeline aimed at detecting BCAs and associated biologically-active compounds, which included: (A) isolation of multidrug-resistant desert soil bacteria and root-associated bacteria from medicinal plants; (B) invitro screening of bacterial isolates against known plant, animal and human pathogens; (C) nextgeneration sequencing of isolates that displayed antagonistic activity against at least one of the model pathogens and (D) in-planta screening of promising BCAs in a model bean-Sclerotiumrolfsii system. The BCA genome data were examined for presence of: i) secondary metabolite encoding genes potentially linked to the anti-pathogenic activity of the isolates; and ii) rhizosphere competence-associated genes, associated with the capacity of microorganisms to successfully inhabit plant roots, and a prerequisite for the success of a soil amended BCA. Altogether, 56 phylogenetically-diverse isolates with bioactivity against bacterial, oomycete and fungal plant pathogens were identified. These strains were sent to Auburn University where bioassays against a panel of animal and human pathogens (including multi-drug resistant pathogenic strains such as A. baumannii 3806) were conducted. Nineteen isolates that showed substantial antagonistic activity against at least one of the screened pathogens were sequenced, assembled and subjected to bioinformatics analyses aimed at identifying secondary metabolite-encoding and rhizosphere competence-associated genes. The genome size of the bacteria ranged from 3.77 to 9.85 Mbp. All of the genomes were characterized by a plethora of secondary metabolite encoding genes including non-ribosomal peptide synthase, polyketidesynthases, lantipeptides, bacteriocins, terpenes and siderophores. While some of these genes were highly similar to documented genes, many were unique and therefore may encode for novel antagonistic compounds. Comparative genomic analysis of root-associated isolates with similar strains not isolated from root environments revealed genes encoding for several rhizospherecompetence- associated traits including urea utilization, chitin degradation, plant cell polymerdegradation, biofilm formation, mechanisms for iron, phosphorus and sulfur acquisition and antibiotic resistance. Our labs are currently writing a continuation of this feasibility study that proposes a unique pipeline for the detection of BCAs and biopesticides that can be used against phytopathogens. It will combine i) metabolomic screening of strains from our collection that contain unique secondary metabolite-encoding genes, in order to isolate novel antimicrobial compounds; ii) model plant-based experiments to assess the antagonistic capacities of selected BCAs toward selected phytopathogens; and iii) an innovative next-generation-sequencing based method to monitor the relative abundance and distribution of selected BCAs in field experiments in order to assess their persistence in natural agro-environments. We believe that this integrated approach will enable development of novel strains and compounds that can be used in large-scale operations.
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Shpigel, Nahum, Raul Barletta, Ilan Rosenshine, and Marcelo Chaffer. Identification and characterization of Mycobacterium paratuberculosis virulence genes expressed in vivo by negative selection. United States Department of Agriculture, January 2004. http://dx.doi.org/10.32747/2004.7696510.bard.

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Mycobacterium avium subsp. paratuberculosis (MAP) is the etiological agent of a severe inflammatory bowel disease (IBD) in ruminants, known as Johne’s disease or paratuberculosis. Johne’s disease is considered to be one of the most serious diseases affecting dairy cattle both in Israel and worldwide. Heavy economic losses are incurred by dairy farmers due to the severe effect of subclinical infection on milk production, fertility, lower disease resistance and early culling. Its influence in the United States alone is staggering, causing an estimated loss of $1.5 billion to the agriculture industry every year. Isolation of MAP from intestinal tissue and blood of Crohn's patients has lead to concern that it plays a potential pathogenic role in promoting human IDB including Crohn’s disease. There is great concern following the identification of the organism in animal products and shedding of the organism to the environment by subclinically infected animals. Little is known about the molecular basis for MAP virulence. The goal of the original proposed research was to identify MAP genes that are required for the critical stage of initial infection and colonization of ruminants’ intestine by MAP. We proposed to develop and use signature tag mutagenesis (STM) screen to find MAP genes that are specifically required for survival in ruminants upon experimental infection. This research projected was approved as one-year feasibility study to prove the ability of the research team to establish the animal model for mutant screening and alternative in-vitro cell systems. In Israel, neonatal goat kids were repeatedly inoculated with either one of the following organisms; MAP K-10 strain and three transposon mutants of K-10 which were produced and screened by the US PI. Six months after the commencement of inoculation we have necropsied the goats and taken multiple tissue samples from the jejunum, ileum and mesenteric lymph nodes. Both PCR and histopathology analysis indicated on efficient MAP colonization of all the inoculated animals. We have established several systems in the Israeli PI’s laboratory; these include using IS900 PCR for the identification of MAP and using HSP65-based PCR for the differentiation between MAV and MAP. We used Southern blot analysis for the differentiation among transposon mutants of K-10. In addition the Israeli PI has set up a panel of in-vitro screening systems for MAP mutants. These include assays to test adhesion, phagocytosis and survival of MAP to/within macrophages, assays that determine the rate of MAPinduced apoptosis of macrophages and MAP-induced NO production by macrophages, and assays testing the interference with T cell ã Interferon production and T cell proliferation by MAP infected macrophages (macrophage studies were done in BoMac and RAW cell lines, mouse peritoneal macrophages and bovine peripheral blood monocytes derived macrophages, respectively). All partners involved in this project feel that we are currently on track with this novel, highly challenging and ambitious research project. We have managed to establish the above described research systems that will clearly enable us to achieve the original proposed scientific objectives. We have proven ourselves as excellent collaborative groups with very high levels of complementary expertise. The Israeli groups were very fortunate to work with the US group and in a very short time period to master numerous techniques in the field of Mycobacterium research. The Israeli group has proven its ability to run this complicated animal model. This research, if continued, may elucidate new and basic aspects related to the pathogenesis MAP. In addition the work may identify new targets for vaccine and drug development. Considering the possibility that MAP might be a cause of human Crohn’s disease, better understanding of virulence mechanisms of this organism might also be of public health interest as well.
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