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Quevedo, Camilo E. "Design and synthesis of Quinazolinone-based libraries for inhibitation of Kinase activity and hit-to-lead optimisation of Wnt pathway inhibitors". Thesis, Institute of Cancer Research (University Of London), 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.510367.
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Borzakian, Sibyline. "Identification et développement chimique d'inducteurs de protéines immunorégulatrices (SLPI et IL-10) à visée thérapeutique". Electronic Thesis or Diss., université Paris-Saclay, 2024. http://www.theses.fr/2024UPASF012.
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Les travaux réalisés durant cette thèse ont été scindés en trois parties distinctes, s'inscrivant toutes dans le cadre du développement de composés à visée thérapeutique. La première partie de ce manuscrit est consacrée à l'identification d'inducteurs de SLPI (Secretory Leucocyte Protease Inhibitor), une protéine principalement produite par les cellules immunitaires et épithéliales, et possédant de nombreuses propriétés biologiques prometteuses. Un criblage phénotypique a donc été mis en œuvre à partir de deux chimiothèques académiques et a mené à l'identification de 5 hits, capables d'induire la production de SLPI par les lymphocytes B. Ces travaux ont donc permis d'ouvrir la voie aux applications thérapeutiques potentielles de ces composés, notamment dans le cadre du développement de traitements antibiotiques ou anti-inflammatoires. La deuxième partie de ce manuscrit est consacrée à l'identification d'un pharmacophore d'inducteurs d'Interleukine-10 (IL-10), une cytokine produite par les cellules immunitaires, et ayant pour rôle principal la régulation de l'immunité. Préliminairement à ces travaux de thèse, un criblage phénotypique a permis d'identifier des inducteurs de la production d'IL-10 par les lymphocytes B à des fins de thérapie cellulaire visant à réduire les symptômes de la sclérose en plaque. Les travaux réalisés dans le cadre de cette thèse ont donc consisté en l'optimisation hit-to-lead du composé le plus prometteur, afin d'identifier un pharmacophore d'inducteurs d'IL-10, via l'établissement de relations structure-activité robustes. Durant ces travaux, 240 analogues ont été synthétisés. Enfin, la troisième partie de ce manuscrit est consacrée au développement d'une méthodologie de synthèse par voie photochimique, pour l'accès à des composés hétérocycliques originaux. Cette méthodologie ne nécessitant ni chauffage, ni catalyseur métallique, s'inscrit donc pleinement dans le développement d'une chimie plus verteThe work carried out during this thesis has been divided into three distincts parts, all relating to the developpement of compounds for therapeutic use. The first part of this manuscript is devoted to the identification of inducers of Secretory Leucocyte Protease Inhibitor (SLPI), a protein mainly produced by immune and epithelial cells, with numerous promising biological properties. A phenotypic screening was conducted using two academic chemical libraries, leading to the identification of 5 hits able of inducing SLPI production by B cells. This work paved the way for potential therapeutic applications of these compounds, particularly in the development of antibiotic or anti-inflammatory treatments. The second part of this manuscript is dedicated to identifying a pharmacophore for inducers of Interleukin-10 (IL-10), a cytokine produced by immune cells, whose main role is the regulation of immunity. Prior to this thesis, a phenotypic screening was conducted to identifiy inducers of IL-10 production by B cells for use in cell therapy to reduce symptoms of multiple sclerosis. This thesis work involved hit-to-lead optimization of the most promising compound to identify a pharmacophore for IL-10 inducers through the establishment of robust structure-activity relationships. During this phase, 240 analogs were synthetized. Finally, the third part of this manuscript focuses on the development of a photochemical synthesis methology for accessing original heterocylic compounds. This methology, requiring neither heating nor metallic catalysts, aligns with the development of greener chemistry
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Samson, Samantha. "Profilage in silico de la protéine multifonctionnelle Mfd, une cible thérapeutique innovante dans la lutte contre l'antibiorésistance bactérienne". Electronic Thesis or Diss., université Paris-Saclay, 2024. http://www.theses.fr/2024UPASL125.
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Face à la montée préoccupante de la résistance aux antibiotiques, la recherche de nouveaux antimicrobiens constitue un enjeu de santé urgent. Nous avons identifié la protéine bactérienne Mutation Frequency Decline (Mfd) comme étant une cible thérapeutique innovante pour le développement de nouveaux médicaments. Un criblage in silico à haut débit a été réalisé, dans un premier temps, afin de sélectionner des molécules pouvant se lier spécifiquement au site actif de la protéine et inhiber son activité, empêchant donc la résistance bactérienne face au stress immunitaire de l'hôte. Les molécules identifiées se sont révélées efficaces in vitro et efficaces et non toxiques in vivo, dans un modèle d'infection chez l'insecte, sur au moins deux pathogènes bactériens. Ces données préliminaires ont constitué une preuve de concept du potentiel innovant de ces molécules et ont également servi de base aux travaux présentés dans cette thèse.L'objectif principal de ce travail était l'identification des interactions moléculaires critiques entre ces molécules inhibitrices et le site actif de Mfd chez E. coli, ainsi que l'élargissement de cette analyse aux pathogènes prioritaires du groupe ESKAPE. En conséquence de quoi, un modèle optimal d'inhibiteur a été déterminé et ses dérivés sont actuellement testés in vitro et in vivo en tant que potentiels agents antimicrobiens. En parallèle, l'analyse de la séquence et de la structure de Mfd, provenant de souches environnementales et cliniques, met en évidence les caractéristiques d'une corrélation moléculaire entre la séquence de Mfd et le phénotype de virulence du pathogène. La confirmation in vitro est actuellement en cours d'évaluation. Enfin, mon objectif final est de repositionner la fonction motrice de Mfd dans un cadre plus large de remodelage conformationnel et fonctionnel afin de mieux comprendre cette cible et son rôle dans la réparation par excision de nucléotides. En produisant plusieurs simulations de dynamique moléculaire sur des « linkers » clés qui relient les principaux modules fonctionnels de Mfd, l'investigation de leur flexibilité intrinsèque et de leur conservation vise à récapituler le remodelage extensif des conformations de Mfd au cours de son cycle fonctionnel, tel qu'il a été décrit précédemment par cryo-EM. Cela a pour but de documenter dans quelle mesure ces linkers, qui relient cette protéine multi-modulaire, sont plus que de simples "connecteurs" et portent, dans leur séquence et leur longueur, des propriétés internes leur permettant d'adopter des états discrets garantissant la transition boucle-hélice nécessaire au bon fonctionnement de MfdIn an alarming context of antibiotic resistance, the search for new antimicrobials is an urgent health issue. We had identified the bacterial protein Mutation Frequency Decline (Mfd) as an innovative target for the development of new drugs. A high throughput in silico screening was initially performed in order to select molecules specifically binding to the active site of the target and inhibiting its activity, thereby preventing bacterial resistance to host immune stress. The identified hits were shown to be efficient in vitro and efficient and non-toxic in vivo, in an insect model of infection on at least two bacterial pathogens. These preliminary data have constituted a proof of concept of the innovative potential of these hits and were also the basis of this thesis.The main objective of this work was the identification of the critical molecular interaction found between those hits and the active site of Mfd in E. coli and also enlarged to the priority pathogens of the ESKAPE group. As a result, an optimal inhibitor scaffold was determined and its derivatives are currently tested in vitro and in vivo as potential antimicrobial agents. In parallel, the sequence and structure analysis of Mfd, from environmental and clinical strains, showcase the basic features of a molecular correlation between Mfd sequence and virulence phenotype. The in vitro confirmation is currently being evaluated. Finally, my goal reposition this motor function of Mfd into a larger conformational and functional remodeling of Mfd in order to get a better understanding of this target and its role in the Nucleotide Excision Repair. Using molecular dynamics simulation on distinguished linkers that connect the main functional modules of Mfd, the investigation of their intrinsic flexibility and resilience to recapitulate the extensive remodeling of Mfd conformations within its functional cycle that has been previously described by cryo-EM. This aims to document to which extent the linkers that connect this multi-module protein are more than "linkers" and harbor, in their sequence and length, internal properties to adopt discrete states that guarantee disorder-to-coil transition to assure the functional machinery of Mfd
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Papadatos, George. "Data mining for lead optimisation". Thesis, University of Sheffield, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.556989.
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The recurring theme of this thesis is the application of diverse data mining and chemoinformatics techniques to structural and experimental property data, and particularly to data produced during the stage of drug discovery called lead optimisation. The work reported here seeks to provide more than one rational answer to the real-life issues routinely facing medicinal chemists. The thesis is divided into three parts: In the first part, several methodologies are described which facilitate the automatic mining of temporal, hierarchical lead optimisation data from the archives. Then, these data are appropriately used to provide informative visualisations, with regard to the exploration of chemical space, both locally (i.e. on a chemical array level) and globally (i.e. in the whole project). Finally, several ways of assessing the progress of a particular lead optimisation project are investigated. The second part of the thesis compares and assesses the relative merits of two computational methods that quantify the neighbourhood behaviour of a descriptor. The main conclusions of this part are two-fold: firstly, the optimality criterion method is demonstrated to be a suitable way to select descriptors for the systematic exploration of chemical space during array-based lead optimisation; secondly, regarding the actual neighbourhood behaviour performance exhibited by twelve types of fingerprints, it is shown that circular-based ones perform consistently better than the others and, notably, at a much lower similarity threshold. The third part focuses on explicit structural transformations between molecular pairs and their impact on properties such as hERG channel blocking, solubility and lipophilicity. More importantly, the study investigates the context of a transformation and its role on the impact of a particular modification. Using substructural descriptors to represent the context of a transformation, and considering both the local and the global environment, several contextsensitive cases are identified and rationalised. Overall, it is demonstrated that the inclusion of contextual information can enhance the predictive power of matched molecular pair analysis. Several context-sensitive examples are also identified in publicly available data.
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Neiström, Linda. "Characterisation of Used Lead-Acid Batteries for Feed Optimisation in Secondary Lead Production". Thesis, Luleå tekniska universitet, Institutionen för samhällsbyggnad och naturresurser, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:ltu:diva-70740.
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Used lead-acid batteries are the main raw material in secondary lead production. Technologicalprogress in the car industry, have raised concerns regarding the lead-acid battery’s leading positionas electrochemical storage system in the future. However, the lead-acid battery industry isadvancing with innovations, such as hybrid and micro-hybrid vehicles, and is believed to have acontinued important role in the rechargeable battery market. Lead is one of the most investigatedmetal due to concerns from society regarding the negative effect on human health and theenvironment. Consequently, that has led to tighter controls and regulations of the lead processingindustry which, in turn, has led to technological improvement concerning design and operation ofthe lead processing plants. Used lead-acid batteries have a complex composition with a variety ofcomponents made of lead (i.e., metallic, oxide or sulphate) and non-lead materials (plastics andelectrolyte). Traditionally, battery recycling is done without separating those components.However, to optimise the use of resources and decrease the environmental impact of secondarylead production, a pre-treatment step to the batteries recycling is desired. The pre-treatment iscomprised of breaking the batteries and separation of the battery components. The aim of the present thesis, was to study the components of a used lead-acid battery, which willbe the outgoing material of a future plastic separation plant at Boliden Bergsöe, and their effect onthe process. Furthermore, the study aimed at investigating the possibilities to adjust the feedcomposition for further process optimisation and improvement of the process quality in terms ofenergy usages and environmental impact. This was done by characterise, through qualitative andquantitative composition and mass distribution, the fractions in a used lead-acid car battery. Four lead-acid car batteries were provided for dismantling to study mass distribution, and toliberate the components for further analysis. The analytical techniques used in this study werequalitative and quantitative (Rietveld) XRD analysis, SEM-EDS and TGA. The result showed thatoverestimated amount of battery separators (PE) has been used at production planning in energyandemission calculations, which can cause financial losses due to overpaid emission tax. The pastefraction showed a large variation in mass between the studied batteries and consists mostly ofPbSO4. Large variation in the paste mass may cause uneven sulphur emission from smelter.Consequently, this reinforces the need for implementation of the separation of the battery feed fora better control of the paste addition to the smelter. When PE decomposes in the shaft furnace the remaining ash will mainly consist of silica, whichwill affect the sulphur uptake in the shaft furnace. The large content of silica leads to a lower energycontribution to the process; however, a lower content of hydrocarbons leads to lower CO2emissions. If a desulphurisation of the pastes would be implemented, it is believed to affect theprocess through a decreased need of coke and iron. A reduced usage of coke and iron would lowerthe production costs and lead to decreased CO2 emissions. A desulphurisation will also decreasethe lead sulphate content in the feed, thus lead to better control of the sulphur emissions. This study provides additional support and further insight into composition and mass distributionof the components in a lead-acid battery. Furthermore, the study indicates possible impact of thefuture separation on the new feed properties and on the subsequent processing.
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Yglesias, Tatiana. "Application of process analysis and optimization tools in hit-to-lead and lead optimization phases of drug discovery at EPP, NIBR". Thesis, Massachusetts Institute of Technology, 2010. http://hdl.handle.net/1721.1/59882.
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Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering; and, (M.B.A.)--Massachusetts Institute of Technology, Sloan School of Management; in conjunction with the Leaders for Global Operations Program at MIT, 2010.Cataloged from PDF version of thesis.
Includes bibliographical references (p. 82-84).
Given that research is based on innovation, it has been believed that its activities can only be optimized with equipment upgrade, increment in personnel scientific knowledge, development of new analytical software and/or changing the areas of study. After realizing the limited results achieved with these approaches, lab representatives started to notice the opportunity of introducing process optimization tools, such as Lean and Six Sigma, which showed success in manufacturing environments,. This project analyzes the interrelation between process and results, providing a clear explanation of cause and effect conditions, and a concise list of areas for improvement. Specifically, the document defines a measurement system using process maps and key performance indicators (KPIs). With this, the document describes the current state through historic trends, provides a complete data and root cause analysis for current state description, and provides a process capability study for the available indicators. Implementation of the steps mentioned above show how focus in lab turnaround times have been deviating attention from more impactful improvements, which can greatly affect overall drug discovery duration. Also, the analysis identifies that constant technology changes caused constant adaptation of process procedures, which generated non-value added activities. These non-value added activities today occupy about 50% of a lab associate's time. Lastly, historic data evaluation shows that root cause statistical analysis is limited by the presence of a combination of special and common cause variations. Some of the project recommendations include: incorporation of chemist's knowledge about compound potency, integration of equipment and software information, change in booking system, incorporation of assay and plate criteria, definition of standard procedures for specific activities, and integration of assay development and data submission tools. Overall, these changes can lead to a 50% reduction in the profiling times greater than 60 days, decrease of 62% and 60% in Compound Manager (CM) and Compound Profiler (CP) non-value added times respectively, 30% decrease in CM and CP total duration per assay plate, and increase in profiling time stability and predictability. Despite the fact that timing and scale of available resources will impact the realized benefits, the proposed framework gives EPP the opportunity to assess the improvements by their effect and alignment with goals.
by Tatiana Yglesias.
M.B.A.
S.M.
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Voitovich, Iuliia. "Les inhibiteurs d'interaction protéine-protéine, une stratégie innovante en cancérologie". Thesis, Aix-Marseille, 2018. http://www.theses.fr/2018AIXM0701.
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Les protéines BET, modules impliqués dans la régulation épigénétique, jouent un rôle essentiel dans le développement du cancer. Actuellement plusieurs inhibiteurs de protéines BET font l'objet d'essais cliniques pour le traitement de différents types de cancer. Une des limitations au développement clinique est l'impact général de la modulation génique induite par des inhibiteurs de type ‘pan-BET’ non sélectifs. Un ciblage individuel des protéines BET et la discrimination des domaines BD1 et BD2 conduiraient à un effet transcriptionnel plus spécifique limitant les effets secondaires et l’apparition de résistance. Le criblage d’une chimiothèque focalisée sur les interactions protéine-protéine a permis d’identifier deux molécules avec des profils de sélectivité uniques. Une étude de SAR a révélé le fragment minimal nécessaire à l’interaction ligand-protéine. La résolution de la structure cristallographique en complexe avec Brd4(BD1) a permis de valider nos interprétations et de développer des inhibiteurs BET plus puissants et sélectifs. Une stratégie de synthèse originale orientée vers une diversité structurale (DOTS) combinant le criblage virtuel et l’élaboration automatisée de bibliothèques focalisées a été utilisée. Ce travail a découvert un inhibiteur optimisé de BD1 avec une affinité de 100x supérieure à la molécule initiale et un ratio de sélectivité BD1 vs BD2 égale à 300. L’activité cellulaire d’inhibition du pro-oncogène c-Myc, au µM, a permis de valider le composé en tant que sonde moléculaire. Des études in vitro et in vivo permettront d'élucider le rôle biologique individuel de chaque BD et de valider l'intérêt de leurs développement en cliniqueBET-proteins, acting as epigenetic readers, play an essential role in cancer development. To date, numerous potent inhibitors disrupting BET functions have been discovered, including several of them that are undergoing clinical trials for the treatment of different types of cancer. The common drawback limiting their use in clinical practice is an inability to distinguish between BET-members that may cause side effects and resistances. The selective targeting of individual BET and the discrimination between BD1 and BD2 present an opportunity to achieve more selective transcriptional effect. A midthroughput screening of previously designed chemical library allowed identification of two molecules with unique profiles of selectivity that have never been observed. An undertaken structure-based program revealed a minimum scaffolds necessary for binding. Taking together with resolved X-Ray structures it allowed the development of more potent and selective BET inhibitors by DOTS (diversity oriented target focused synthesis) strategy, combining virtual screening and diversity oriented library design. This optimization led to a potent inhibitor with up to 100-fold improvement of affinity to the target and up to 300-fold selectivity toward BD1. Dose-response downregulation of c-Myc levels in low micromolar range in cell assays allowed the validation of the identified molecule as a chemical probe. Further comprehensive in vitro and in vivo evaluations of this compound will enable elucidating the biological role of each bromodomain and a validation of the interest toward the development of selective inhibitors in clinic
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Mariani, Alessandro. "Optimisation of valve regulated lead acid battery design for high power applications". Thesis, University of South Wales, 2017. https://pure.southwales.ac.uk/en/studentthesis/optimisation-of-valve-regulated-lead-acid-battery-design-for-high-power-applications(f8316110-ebc1-4f0b-9e1b-4a66d7e50564).html.
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Filippi, Andrea <1990>. "An application of Genetic Algorithms for the Lead Molecule Optimisation. (Titolo provvisorio)". Master's Degree Thesis, Università Ca' Foscari Venezia, 2016. http://hdl.handle.net/10579/9366.
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Lead Molecule Optimisation and the process of Drug Design are very difficult problems, demanding an huge investment in terms of resources and experimentation. The standard approach requires iterations of long synthesis and testing cycles as well as formulations, which are hard and complex tasks. In this thesis are presented, in the first chapters, an analysis of Nature inspired computation and the problem of Lead Molecule Optimisation; lately it is proposed a method to address such problem. It is the Genetic Algorithm Optimisation (GAO) method, which will be applied to a set of experimental data of fitness values and molecule fragments. The dataset is provided by the European Center for Living Technology (ECLT). The GAO is used to find an optimal solution for the development of a particular drug (MMP-12 inhibitors). A total of 120 molecules are tested over 6 generations; the results show that the algorithm works as intended by reaching the optimum in an acceptable amount of time, required for the computation. The good performance of the GAO method is analysed and shown in the thesis with its capacity to reach the desired optimum value using the data set provided.
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Moffat, Kirstin. "Development of computational methods for 3D similarity and structure-based design techniques in lead optimisation". Thesis, University of Sheffield, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.434521.
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Fookes, William. "Optimisation of a pillow production line applying Lean principles". Thesis, KTH, Industriell produktion, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-102777.
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Manufacturing companies throughout the world are interested in reducing the time between a customer placing an order and them receiving the payment for that order. This premise is something that is a central characteristic for the Lean philosophy, and is one of the reasons to apply it. Today manufacturers around the world are embracing Lean techniques in order to reduce waste and increase productivity, and also increase the inventory turns, which reflects in an improvement of cash flow for the company. Nowadays, with all the financial turmoil, every company is looking forward to reduce the inventories, to work with Just in Time supply chains, to develop production systems that reduce the scrap and produce only what is needed, saving space, and freeing up time to work on new design and be at the edge of innovation in order to gain market share and keep improving. This master thesis is focused on implementing the Lean principles in a pillow production line, in order to achieve it, a series of techniques to assess the facility where implemented, which allowed to understand how the facility was working, where is the bottleneck, and to understand the function of it as a system, avoiding to focus on a single point but viewing it as a whole, where each part contributes in a specific and unique way, but where all of them are necessary. Applying Lean principles is a daunting task that takes a long time, a never ending trial and error process, because of this the goal of this study is to develop the bases for a Lean transformation, a schedule for the implementation will be developed and proposed to the company, after analyzing the facility. The study reveals that it is possible to reduce the lead-time of the facility in 60%, and avoid the backorders situation that is present in the company, improving also the service level.
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Wylde, Elinor. "Drug metabolism and pharmacokinetics in the lead optimisation of novel positive allosteric modulators of α1 strychnine sensitive glycine receptors". Thesis, University of Liverpool, 2015. http://livrepository.liverpool.ac.uk/2048099/.
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Chronic pain is a condition that is thought to affect roughly 8 million people in the UK. It is classified as pain that persists for more than 6 months. Chronic pain is commonly associated with depression, insomnia, anxiety and poor quality of life. Many treatments for chronic pain are accompanied by numerous debilitating side-effects, this in combination with insufficient pain relief means that approximately 50% of patients will discontinue their treatment. Most sufferers choose to live with the pain rather than deal with numerous adverse-effects. There is a great need for new therapeutics that are specifically designed to target the underlying mechanisms of chronic pain, therefore providing safer and more effective treatments. One such mechanism is the down-regulation of strychnine-sensitive glycine receptors (SSGRs) localised in the dorsal horn. Glycinergic activity is known to be inhibitory and artificial stimulation can produce analgesia. Positive allosteric modulators acting on α1 SSGRs may able to compensate for the inhibitory glycinergic activity that is reduced in chronic pain. Previous work within the group lead into the identification of propofol analogues designed to be novel positive allosteric modulators of α1 SSGRs. Work presented in this thesis describes the generation and optimisation of these analogues with a focus of drug metabolism and pharmacokinetics. The hit to lead process has resulted in the development of a lead compound that is highly potent at the target, has excellent pharmacokinetic and safety profiles and is able to produce high levels of analgesia in an animal model of neuropathic pain.
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Leung, Suet Ching. "New and established drug targets for malaria chemotherapy from lead optimisation of 2-pyridyl quinolone PfNDH2 inhibitors to semi-synthetic pyrrole Mannich base artemisinin derivatives". Thesis, University of Liverpool, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.577488.
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The rapid development of resistance to currently deployed antimalarial drugs has raised the desperate need for new chemotherapies, preferably with novel therapeutic target. This thesis explores the synthesis of novel quinolone compounds and artemisinin derivatives targeting the mitochondrial electron transfer chain (ETC) and the haemoglobin degradation of Plasmodium falciparum respectively. The respiratory chain of the human malaria is an attractive target for antimalarial drugs. It is believed that the collapse of the mitochondrial potential will shut down the metabolism and malaria parasite de novo synthesis of pyrimidines, ultimately leading to the death of parasite. The bc1, (Complex III) inhibitors are being studied by many scientists, with recent studies targeting PfNDH2 due to its potential as a therapeutic target (Humans lack this enzyme in the respiratory chain). Following the hit to lead optimisation of chemical name here CK-2-68 against the PfNDH2 enzyme in the group, a series of quinolones were designed to improve the ClogP and aqueous solubility. Analogues in this series were synthesised in less than six-step. Our strategy for reducing the ClogP of the original series involves the incorporation of heterocycles into the C and 0 rings of the side chain. Work describes in this thesis was principally cover the 2-pyridyl series of compounds. Two of these analogues have ICso values in the nanomolar range versus PfNOH2 enzyme and 307 strain of Plasmodium falciparum. Further in vivo studies showed that these two analogues have notable ED50/ED90 against Plasmodium berghei (NS Strain) following oral administration. A series of 6-substituted quinolone esters and pyrrolidine-fused quinolones were also prepared for targeting bc1 complex. They were tested in vitro to explore their structure-activity relationship (SAR). The 6-substituted quinolone ester were synthesised in four steps employing the Gould-Jacobs method. It was noticed that the 3-ester functionality and its steric size are essential for good activity. The 6- substituted quinolone esters possess moderate antimalarial activity with the lead analogue IC50 of 40.4 nM. The 6-substituted quinolone esters were compared head to head with the 7-series of analogues. In an attempt to enhance solubilities, pyrrolidine-fused quinolones were synthesised using Winterfeldt oxidation. Although the compounds were poorly soluble, the potent in vitro result of one of the analogues underlines the potential of the template for further study. Artemisinin and its semi-synthetic derivatives are the most effective drugs in malarial chemotherapy. Despite of their high therapeutic indices, they have poor bioavailability and short half-lives in general. To improve the aqueous solubility and metabolic stability, a series of semi-synthetic C-10 pyrrole Mannich artemisinin derivatives were prepared in 2 steps from dihydroartemisinin. These analogues have demonstrated nanomolar antimalarial activity against the 3D7 strain and Kl strain of Plasmodium falciparum in vitro with high therapeutic indices. Further in vivo studies showed that three of the analogues have excellent ED50/ED90 indicating their overall in vitro and in vivo drug profiles are superior to those of clinically used artemether and artesunate.
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Slama, Ilhem. "Modélisation et optimisation de problème de planification de désassemblage dans un environnement incertain". Thesis, Ecole nationale supérieure Mines-Télécom Atlantique Bretagne Pays de la Loire, 2020. http://www.theses.fr/2020IMTA0192.
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Notre projet de recherche propose de modéliser et d’optimiser le problème lié à la détermination du plan de démontage des produits enfin de vie tout en satisfaisant les demandes en composants sur un horizon de planification donné. Les travaux présentés dans ce manuscrit portent sur la planification de désassemblage dans un contexte certain et incertain. Nous avons considéré trois modélisations principales avec leurs approches de résolution : (i) une modélisation déterministe multi-période qui traite une nomenclature de produit multi-niveau avec le partage des composant qui cherche à maximiser le profit total. Un programme linéaire mixte en nombres entiers est proposé pour résoudre d’une façon optimale le problème, (ii) une modélisation stochastique monopériode pour traiter le cas d’une nomenclature de produit à deux niveaux et un seul type de produit. Les délais de remise à neuf sont supposés stochastique avec des distributions de probabilité quelconques. Le modèle cherche à minimiser l’espérance mathématique des coûts de stockage et de rupture des composants. Une approche de résolution exacte basée sur le modèle ”Newsboy" est développée pour résoudre le problème, et (iii) un modèle stochastique multi-période qui traite l’incertitude des délais de remise à neuf de chaque composant à chaque période est étudié quand le croisement des ordres est autorisé. La programmation linéaire mixte en nombres entiers stochastique, la simulation Monte Carlo et l’agrégation des scénarios sont proposées pour résoudre ce type de problème. Les performances des méthodes de résolution développées sont présentées en analysant les résultats d’optimisation sur un ensemble d’instances générées aléatoirementOur research proposes to model and optimize the disassembly lot-sizing problem. The contributions presented in this manuscript focus on disassembly planning in certain and uncertain context. We have considered three main models with their resolution approaches: (i) a deterministic multi-period modeling that deals with a multilevel product structure with a commonality of components that aims to maximize total profit. A Mixed Integer Linear Programming (MILP) model is proposed to optimally solve the problem, (ii) a single period stochastic model with a two-level disassembly system and a single type of end-of-life product under random refurbishing lead times. This model seeks to minimize the total expected cost, composed of inventory and backlog costs. A Newboy approach is proposed to solve the problem, and (iii) a multi-period stochastic model which deals with the uncertainty of refurbishing lead times when order crossover is considered. Stochastic Mixed Integer Linear Program, Monte Carlo simulation and scenario aggregation approaches are proposed to solve the proposed model. The performances of the proposed resolution approaches are presented by analyzing the optimization results on a set of randomly generated instances
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Lim, Lâm Laurent. "Nouveau modèle de planification industrielle et commerciale avec approvisionnement long dans l'industrie automobile : approche par simulation-optimisation". Thesis, Grenoble, 2014. http://www.theses.fr/2014GRENI019/document.
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Face à un environnement incertain et une internationalisation croissante de la chaîne logistique, la planification industrielle et commerciale (PIC) permet d’adapter efficacement les capacités industrielles à la demande du marché. Dans cette étude, nous présentons un modèle original de PIC utilisant des contraintes de flexibilité, pour améliorer la coordination entre les fonctions commerciales et logistiques. Un premier modèle de simulation permet d’étudier la dynamique du système ainsi que l’impact des différents paramètres sur les performances en termes de coûts et de satisfaction client. Afin d’étudier les politiques optimales, nous proposons un nouveau modèle de simulation-optimisation multi objectif. Différentes méthodes d’optimisation sont comparées, et plusieurs recommandations sont émises pour l’implémentation pratique de notre solution. Enfin, nous comparons les performances de plusieurs politiques de gestion des stocks lorsqu’elles sont couplées avec notre méthode de PIC flexible. À partir de données réelles du constructeur automobile Renault, nous présentons une étude comparative détaillée. Nous proposons plusieurs préconisations pratiques sur le type de politiques à privilégier selon les caractéristiques du système. Ces travaux de recherche sont particulièrement pertinents et applicables à d’autres industries confrontées à de fortes exigences commerciales,une faible visibilité sur la demande future et des approvisionnements longsFace to uncertain environment and growing globalization of the supply chains, the salesand operations planning (S&OP) aims to adapt efficiently the industrial capacities to themarket demand. In this research, we present an original S&OP model that uses flexibilityconstraints to improve the coordination between sales and logistics functions. A first simulationmodel is developed to study the system dynamics and the impact of different parameters onsystem’s performance in terms of costs and customer satisfaction. We introduce a multiobjectivesimulation-optimization model to investigate the optimal policies. Several optimization methodsare compared and recommendations are given for the practical implementation of our solution.Then, we compare the performances of several policies for managing parts inventories whenthey are coupled with our flexible S&OP. Based on real data of the automobile manufacturerRenault, we present a detailed comparative study. We present several managerial insights on thetype of policies to favor depending on the system characteristics. This research is particularlyrelevant for other industries that face strict customer requirements, uncertain demand and longprocurement lead time
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Gervais, Emelyne. "Design et optimisation d'une interface fonctionnalisée par des nanoparticules métalliques et des couches organiques électroformées pour la détection de métaux lourds à l'état de traces dans les eaux". Thesis, Toulouse 3, 2017. http://www.theses.fr/2017TOU30258/document.
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Le mercure est un élément reconnu pour sa toxicité pour les êtres humains, pouvant être notamment la cause de maladies neurologiques ou rénales une fois absorbé dans l'organisme. Il est rejeté dans l'environnement, et en particulier dans les eaux de surface, par des phénomènes naturels comme le volcanisme, mais également par le biais des activités humaines liées à l'industrie. Une fois rejeté, il est ingéré par la faune et la flore marine et bioaccumule tout le long de la chaîne alimentaire. Il est alors présent dans les espèces marines prédatrices dans des proportions importantes, mettant en danger la santé de ces espèces animales et exposant les êtres humains à des quantités importantes de mercure dans l'alimentation. La législation Européenne est très stricte en ce qui concerne les taux de mercure autorisés dans les eaux et se base sur des valeurs relevant de la trace voir de l'ultra trace. Les techniques actuelles permettant de détecter de si faibles doses sont efficaces mais possèdent de nombreux inconvénients tel que leur coût ou l'impossibilité de faire des mesures in situ. Les capteurs électrochimiques sont actuellement l'une des alternatives les plus prometteuses pour la détection de ce métal lourd en solution. L'objectif de ces travaux a donc été de mettre au point un capteur électrochimique basé sur la fonctionnalisation d'une électrode en carbone vitreux par des couches organiques et des nanoparticules d'or pour la détection du mercure. Deux types de couches organiques ont été utilisées et les interfaces ainsi développées caractérisées par voltammétrie cyclique et Microscopie Électronique à Balayage. Deux protocoles d'activation des nanoparticules ont été testés. Les performances des interfaces ont été évaluées au regard de la détection de traces de mercure, ainsi que leur stabilité au stockageMercury is known for its toxicity on human beings, causing neurological and kidney diseases when absorbed in the body. It is rejected in the environment, and especially in surface waters, through natural processes like volcanism and human industrial activities. When present in water, it is ingested by marine plants and wildlife and bioaccumulates all along the food chain. It is then present in high proportions in marine predators, jeopardizing their health and exposing human beings to important mercury quantities in the food supply. The European legislation is very strict regarding to allowed mercury levels in waters, and is based on very low values, from traces to ultra traces. Current techniques able to detect such small doses are efficient but suffer from numerous drawbacks like their cost or the impossibility to use them for in situ measurements. Electrochemical sensors appear to be one of the most interesting alternatives for detection of this heavy metal in aqueous solution. The aim of this work was then to develop an electrochemical sensor based on the functionalization of a glassy carbon electrode with organic layers and gold nanoparticles for mercury detection. Two types of organic layers were used and the interfaces were characterised by using cyclic voltammetry and Scanning Electron Microscopy. Two different gold nanoparticles activation processes were tested. The interfaces performances were evaluated for detection of traces of mercury, as well as their storage stability
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Ben, Ammar Oussama. "Planification des réapprovisionnements sous incertitudes pour les systèmes d’assemblage à plusieurs niveaux". Thesis, Saint-Etienne, EMSE, 2014. http://www.theses.fr/2014EMSE0756/document.
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Dans le contexte actuel marqué par l’instabilité des marchés, les clients sont de plus en plus exigeants. un client qui n’est pas approvisionné à une date souhaitée peut soit remettre son achat à plus tard, soit aller chercher le produit chez un concurrent. de plus, l’entreprise doit faire face à de multiples imprévisibilités internes, de la concurrence ou d’événements extérieurs. ces aléas induisent de l'incertitude dans la planification de la production et génèrent des sources nombreuses de retard, de désynchronisation et de pertes de productivité. ce travail de thèse s’intègre dans la problématique de la planification de la production dans un environnement incertain. nous étudions des problèmes de la planification des réapprovisionnements pour un système d’assemblage à plusieurs niveaux, quand les délais d’approvisionnement sont incertains. nous avons choisi comme indicateur de performance l’espérance du coût total moyen qui est égal à la somme du coût de stockage des composants, le coût de rupture du produit fini et le coût de stockage du produit fini. des propriétés théoriques, des modèles analytiques ainsi que des méthodes d’optimisation ont été proposés. nous avons montré que la résolution du problème ne dépend pas seulement de la méthode de résolution et du nombre de niveaux, mais aussi du coût de rupture en produit fini et de la structure du système d’assemblageIn the current industrial context, the offer is largely higher than the demand. Therefore, the customers are more and more exigent. To distance themselves, companies need to offer to their customers the best quality products, the best costs, and with controlled lead times as short as possible. Last years, the struggle for reducing costs was accentuated within companies. However, stocks represent an important financial asset, and therefore, it is essential to control them. In addition, a bad management of stocks led either to delays in delivery, which generate additional production costs, either to the unnecessary inventory. The latter one can occur at different levels (from components at the last level to finished product), it costs money and immobilize funds. That is why, planners have to look for efficient methods of production and supply planning, to know exactly for each component, and when to order and in which quantity.The aim of this doctoral thesis is to investigate the supply planning in an uncertain environment. We are interested in a replenishment planning for multi-level assembly systems under a fixed demand and uncertainty of components lead times.We consider that each component has a fixed unit inventory cost; the finished product has an inventory cost and a backlogging cost per unit of time. Then, a general mathematical model for replenishment planning of multi-level assembly systems, genetic algorithm and branch and bound method are presented to calculate and to optimize the expected value of the total cost which equals to the sum of the inventory holding costs for the components, the backlogging and the inventory holding costs for the finished product. We can state by the different results that the convergence of the GA doesn't depend only on the number of components in the last level but also on the number of levels, the type of the BOM and the backlogging cost for the finished product
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Barcherini, Valentina. "Hit-to-lead optimization of pharmaceutical interesting tryptophanol-derived scaffolds". Master's thesis, 2016. http://hdl.handle.net/10362/84243.
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The indole nucleus is the core structure of many natural and synthetic molecules. In fact, indole-based compounds have been described with different biological activities, ranging from antitumor to antimalarials.
Recent studies made by our research group led to the discovery of one enantiopure tryptophanol-derived oxazoloisoindolinone as novel activator of wild-type p53 and reactivator of mutant-type p53. The first objective of this thesis was centered on the hit-to-lead optimization of this specific derivative. Several alkyl substituents with increasing size and electron withdrawing/donating groups were selected for the protection of the indole nitrogen to assemble a library of new analogues for biological screening. A study of the activity based on chirality revealed one compound to be more active than the hit compound 34. Particularly, compound 34d restores the wt-like growth inhibitory effect to mut p53R280K in a percentage of 86.8%. Finally, the stability-profile of this chemical family was evaluated using compounds 34 and 34e as models.
The second main goal of this thesis was the investigation of new leads as promising antimalarials, based on the recent report that a library of enantiopure indolizinoindolones exhibits in vitro activity against erythrocytic and liver-stages of malaria parasite. Structural derivatization of the hit-compounds was carried out using an enantioselective two-step route, involving an intramolecular cyclization to assemble the final polycyclic indolizinoindolones derivatives. In vitro screening of these tryptophanol-derived tricyclic compounds permitted the identification of two indolizinoindolone small molecules as the most active compounds.
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Baum, Patrick [Verfasser]. "Phenocopy : a strategy to qualify chemical compounds during hit-to-lead and, or lead optimization / vvorgelegt von Patrick Baum". 2010. http://d-nb.info/1007650710/34.
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Hähnke, Volker Dirk [Verfasser]. "Text-based similarity searching for hit- and lead-candidate identification / von Volker Dirk Hähnke". 2010. http://d-nb.info/1011435446/34.
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Zhang, Guanran. "Optical property optimisation of lead sulphide quantum dots". Thesis, 2013. http://hdl.handle.net/2440/82710.
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To improve photovoltaic performance, lead sulphide quantum dots (PbS QDs) have been introduced in the device structure. To achieve enhanced performance by using PbS QDs, it is essential to gain better understanding on the particle size control and surface modification. The aim of this thesis is to gain better understanding of the particle size control, growth kinetics and surface modification of PbS particles to reach optimised properties for possible future applications. The particle size modification and growth kinetics were studied by systematically varying reaction parameters of reaction time, temperature and reactant feed to synthesize a series of PbS QDs with different first exciton peaks. Studying the absorption wavelength and the full-width-at-half-maximum of photoluminescence spectra from different reaction times shows the three-stage growth process from nucleation through particle growth to final size saturation of the QDs. For each of these stages, the particle size and growth rate were found to be determined by reaction temperature and the stabilizer oleic acid concentrations. By analysing the change of absorption peaks with these parameters, the activation energy of the particle growth stage was calculated. A novel surface ligand exchange approach was explored. By attaching the Pb onto the desired ligand functional groups, the formed 'atomic-ligand' could be readily used for solution phase ligand exchange. Tridentate poly(ethylene glycol) methyl ether (mPEG) was used as a model hydrophilic ligand for PbS exchange. The modification of mPEG was confirmed, and the atomic ligand exchange was compared with the conventional ligand exchange by TEM imaging and quantum yield measurement. The results showed quantum yield enhancement of 715% from 2.7% to 22% and particle dispersity in polymer via atomic-ligand exchange compared with traditional method. In conclusion, the thesis demonstrated detailed kinetics study of PbS quantum dots during different particle growth stages. For the first time, activation energy for PbS quantum dots particle growth was reported to be 28.8kJ/mol. A novel ligand exchange approached was first proposed and the quantum yield was observed to enhance by 715% comparing to conventional exchange method. The results from this study provided important results on PbS QDs synthesis and optimization, which would largely facilitate further studies on the understanding of principle PbS QDs growth dynamics and surface modification using various functional groups.Thesis (M.Eng.Sc.) -- University of Adelaide, School of Chemical Engineering, 2013
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Jayaraj, Abhilash. "Development of some novel computational techniques for screening and optimizing hit molecules for protein targeted lead molecule discovery". Thesis, 2018. http://eprint.iitd.ac.in:80//handle/2074/7934.
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