Le docking moléculaire est une méthode permettant de prédire l'orientation d'une molécule donnée relativement à une autre lorsque celles-ci forment un complexe. Le premier algorithme de docking moléculaire a vu jour en 1990 afin de trouver de nouveaux candidats face à la protéase du VIH-1. Depuis, l'utilisation de protocoles de docking est devenue une pratique standard dans le domaine de la conception de nouveaux médicaments. Typiquement, un protocole de docking comporte plusieurs phases. Il requiert l'échantillonnage exhaustif du site d'interaction où les éléments impliqués sont considérées rigides. Des algorithmes de clustering sont utilisés afin de regrouper les candidats à l'appariement similaires. Des méthodes d'affinage sont appliquées pour prendre en compte la flexibilité au sein complexe moléculaire et afin d'éliminer de possibles artefacts de docking. Enfin, des algorithmes d'évaluation sont utilisés pour sélectionner les meilleurs candidats pour le docking. Cette thèse présente de nouveaux algorithmes de protocoles de docking qui facilitent la prédiction des structures de complexes protéinaires, une des cibles les plus importantes parmi les cibles visées par les méthodes de conception de médicaments. Une première contribution concerne l‘algorithme Docktrina qui permet de prédire les conformations de trimères protéinaires triangulaires. Celui-ci prend en entrée des prédictions de contacts paire-à-paire à partir d'hypothèse de corps rigides. Ensuite toutes les combinaisons possibles de paires de monomères sont évalués à l'aide d'un test de distance RMSD efficace. Cette méthode à la fois rapide et efficace améliore l'état de l'art sur les protéines trimères. Deuxièmement, nous présentons RigidRMSD une librairie C++ qui évalue en temps constant les distances RMSD entre conformations moléculaires correspondant à des transformations rigides. Cette librairie est en pratique utile lors du clustering de positions de docking, conduisant à des temps de calcul améliorés d'un facteur dix, comparé aux temps de calcul des algorithmes standards. Une troisième contribution concerne KSENIA, une fonction d'évaluation à base de connaissance pour l'étude des interactions protéine-protéine. Le problème de la reconstruction de fonction d'évaluation est alors formulé et résolu comme un problème d'optimisation convexe. Quatrièmement, CARBON, un nouvel algorithme pour l'affinage des candidats au docking basés sur des modèles corps-rigides est proposé. Le problème d'optimisation de corps-rigides est vu comme le calcul de trajectoires quasi-statiques de corps rigides influencés par la fonction énergie. CARBON fonctionne aussi bien avec un champ de force classique qu'avec une fonction d'évaluation à base de connaissance. CARBON est aussi utile pour l'affinage de complexes moléculaires qui comportent des clashes stériques modérés à importants. Finalement, une nouvelle méthode permet d'estimer les capacités de prédiction des fonctions d'évaluation. Celle-ci permet d‘évaluer de façon rigoureuse la performance de la fonction d'évaluation concernée sur des benchmarks de complexes moléculaires. La méthode manipule la distribution des scores attribués et non pas directement les scores de conformations particulières, ce qui la rend avantageuse au regard des critères standard basés sur le score le plus élevé. Les méthodes décrites au sein de la thèse sont testées et validées sur différents benchmarks protéines-protéines. Les algorithmes implémentés ont été utilisés avec succès pour la compétition CAPRI concernant la prédiction de complexes protéine-protéine. La méthodologie développée peut facilement être adaptée pour de la reconnaissance d'autres types d'interactions moléculaires impliquant par exemple des ligands, de l'ARN… Les implémentations en C++ des différents algorithmes présentés seront mises à disposition comme SAMSON Elements de la plateforme logicielle SAMSON sur http://www.samson-connect.net ou sur http://nano-d.inrialpes.fr/software. / Molecular docking is a method that predicts orientation of one molecule with respect to another one when forming a complex. The first computational method of molecular docking was applied to find new candidates against HIV-1 protease in 1990. Since then, using of docking pipelines has become a standard practice in drug discovery. Typically, a docking protocol comprises different phases. The exhaustive sampling of the binding site upon rigid-body approximation of the docking subunits is required. Clustering algorithms are used to group similar binding candidates. Refinement methods are applied to take into account flexibility of the molecular complex and to eliminate possible docking artefacts. Finally, scoring algorithms are employed to select the best binding candidates. The current thesis presents novel algorithms of docking protocols that facilitate structure prediction of protein complexes, which belong to one of the most important target classes in the structure-based drug design. First, DockTrina - a new algorithm to predict conformations of triangular protein trimers (i.e. trimers with pair-wise contacts between all three pairs of proteins) is presented. The method takes as input pair-wise contact predictions from a rigid-body docking program. It then scans and scores all possible combinations of pairs of monomers using a very fast root mean square deviation (RMSD) test. Being fast and efficient, DockTrina outperforms state-of-the-art computational methods dedicated to predict structure of protein oligomers on the collected benchmark of protein trimers. Second, RigidRMSD - a C++ library that in constant time computes RMSDs between molecular poses corresponding to rigid-body transformations is presented. The library is practically useful for clustering docking poses, resulting in ten times speed up compared to standard RMSD-based clustering algorithms. Third, KSENIA - a novel knowledge-based scoring function for protein-protein interactions is developed. The problem of scoring function reconstruction is formulated and solved as a convex optimization problem. As a result, KSENIA is a smooth function and, thus, is suitable for the gradient-base refinement of molecular structures. Remarkably, it is shown that native interfaces of protein complexes provide sufficient information to reconstruct a well-discriminative scoring function. Fourth, CARBON - a new algorithm for the rigid-body refinement of docking candidates is proposed. The rigid-body optimization problem is viewed as the calculation of quasi-static trajectories of rigid bodies influenced by the energy function. To circumvent the typical problem of incorrect stepsizes for rotation and translation movements of molecular complexes, the concept of controlled advancement is introduced. CARBON works well both in combination with a classical force-field and a knowledge-based scoring function. CARBON is also suitable for refinement of molecular complexes with moderate and large steric clashes between its subunits. Finally, a novel method to evaluate prediction capability of scoring functions is introduced. It allows to rigorously assess the performance of the scoring function of interest on benchmarks of molecular complexes. The method manipulates with the score distributions rather than with scores of particular conformations, which makes it advantageous compared to the standard hit-rate criteria. The methods described in the thesis are tested and validated on various protein-protein benchmarks. The implemented algorithms are successfully used in the CAPRI contest for structure prediction of protein-protein complexes. The developed methodology can be easily adapted to the recognition of other types of molecular interactions, involving ligands, polysaccharides, RNAs, etc. The C++ versions of the presented algorithms will be made available as SAMSON Elements for the SAMSON software platform at http://www.samson-connect.net or at http://nano-d.inrialpes.fr/software.

Dans le contexte économique actuel, les entreprises cherchent à développer de nouvelles stratégies de distribution pour leurs performances logistique. Dans cette quête de performances, les entreprises doivent adapter les stratégies de distribution misent en place avec les typologies de leurs produits. Plusieurs stratégies de distribution existent dans la chaîne logistique de grande distribution. Ces stratégies sont choisies sur la base des caractéristiques des produits, et /ou l'impact sur les performances logistiques. Dans cette thèse, nous étudions l'impact de trois stratégies de distribution, à savoir: stockage traditionnel, cross-docking pick by line et le cross-docking pick by store, sur trois performances de la logistiques, à savoir: le niveau de service, les coûts et le bullwhip effect. En outre, nous analysons l'impact des caractéristiques des produits sur les performances des stratégies de distribution et enfin proposer un cadre pour le choix de la stratégie la plus adaptée pour chaque produit. La chaîne logistique étudiée est composée de trois échelons: Centre de distribution du fournisseur, Centre de distribution du distributeur et les magasins. Basé sur un cas réel, nous effectuons une modélisation des processus, qui nous permet de développer un modèle déterministe de coût Macro et un modèle de simulation. Le modèle de coût macro permet d'évaluer l'impact des stratégies de distribution sur des coûts de la chaîne logistique. Après l'analyse macro des coûts, nous développons un modèle de simulation où nous intégrons les données relatives aux produits (la demande, le volume, etc.). Ce modèle permet une simulation dynamique du système la stratégie la plus adaptée pour chaque produit en fonction de ses caractéristiques et de l'impact sur les performances. A la fin de cette recherche, nous présentons une matrice de choix pour la segmentation des produits et choix de la stratégie de distribution. / Nowadays companies must look to develop new distribution strategies in order to achieve the required performance from their supply chain. In this quest, companies wonder about the consistency of their distribution strategies with the products they are selling. Several types of distribution strategies exist in the retail supply chain. These strategies are chosen based on the products characteristics, and/or the impact on the supply chain performances. In this research, we study the impact of three distribution strategies, namely: traditional warehousing, cross-docking pick by line and cross-docking pick by store, on three supply chain performances, namely: service level, cost and bullwhip effect. In addition, we analyse the impact of the products characteristics on the performances of the distribution strategies and propose a framework for choosing the right strategy for each product. The supply chain studied is composed of three echelons: Supplier Distribution Centre, Retailer Distribution Centre and Stores. Based a real business case, we perform a process modelling, that allows us to develop a deterministic Macro cost model and a simulation model. The macro cost model allows to evaluate the impact of the distribution strategies on the supply chain cost performance. After the macro cost analysis, we develop a simulation model where we integrate the data related to the products (demand, volume, ordering quantities etc.) in the model. This model allows a more dynamic simulation of the system in a large time period and determines the right strategy to select for each product depending on its characteristics and the impact on the performances. At the end of this research, we present a framework for product segmentation and distribution strategy selection.

Submitted by Maike Costa (maiksebas@gmail.com) on 2017-09-13T11:59:49Z No. of bitstreams: 1 arquivototal.pdf: 7758959 bytes, checksum: db745d41b196978192ebc789e25f442b (MD5) / Made available in DSpace on 2017-09-13T11:59:49Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 7758959 bytes, checksum: db745d41b196978192ebc789e25f442b (MD5) Previous issue date: 2016-02-26 / The use of plants for medicinal purposes is one of the oldest forms of medical practice of mankind, emphasizing the alkaloids because they present rich structural and pharmacological properties extensive variety. The drug design is aided by computer based strategies based on linkers or target. When developing new compounds, the structure-based techniques, such as docking, can be applied to study of certain receptor and its corresponding ligand, evaluating bindingprotein interactions. Whereas in the ligand-based methods, a database of known ligands is used, looking for ways to evaluate parameters (molecular descriptors) that can assist in the development of compounds with higher power. This study aimed to perform in silico studies to investigate drug-target interactions with alkaloids derived from natural products and their analogues with relevant pharmacological activity. Different molecular descriptors and methodologies were used in the studies developed. In chapter 2, the interaction of alkaloid bisindolic caulerpine (CLP) was evaluated with the enzyme involved in Alzheimer's disease (AD) monoamine oxidase B (MAO-B), and a database with 109 analogs. It was possible to observe a chemical parameter of inhibition of PLC analogues where the replacement of the radicals must be asymmetric with different polarity. The studies based on the linker and the structure associated with the classification drug-like chemical skeleton suggest that the PLC has potential use in the treatment of AD. In chapter 3, 8 alkaloids isolated Cissampelos sympodialis and 101 derivatives, had their inhibitory potential against enzyme (BACE, GSK-3β and MAO-A) involved in degenerative diseases assessed by in silico methods. consensual analysis showed affinity alkaloids bisbenzilisoquinolinics by BACE, incluindos the roraimine natural alkaloids and simpodialine-β-N-oxide, supporting interest in investigating this skeleton as an antagonist of this enzyme. In Chapter 4 we evaluated the multi-target potential of 148 aphorphinics alkaloids Annonaceae against Leishmania donovani. Six were selected enzymes of this neglected disease for theoretical study, which was associated with experimental four alkaloids available data and integrating the bank, which had pIC50 value inferior to 5.26. The xyloguyelline alkaloid was named as a potential multi-agent target, demonstrating activity against 5 of 6 enzymes evaluated, likely to activity of over 60%. fragment descriptors were used to create model-based binder in a parallel approach with molecular docking to predict the cytotoxic and against topoisomerase II activity azaphenantrene alkaloids in chapter 5. The cytotoxic activity of this skeleton alkaloids are well described in the literature, molecules having activity against several tumor cell lines. The IMB 6 analog and 23 IMB showed interesting activity and selectivity, with MolDock energy similar to liriodenine composed characterized by potent anti-tumor action, but with high toxicity. Important structural information is provided by spectroscopy nuclear magnetic resonance (NMR), and Chapter 6 aimed to discuss the importance of this technique for generating molecular descriptors. Studies that applied successfully in drug design NMR descriptors assisted by computer are described and several QSAR and QSPR having as support data chemical shifts. / A utilização de plantas com fins medicinais é uma das mais antigas formas de prática medicinal da humanidade, enfatizando os alcaloides, por apresentarem rica variedade estrutural e extensa propriedade farmacológica. O desenho de drogas auxiliado pelo computador é fundamentado em estratégias baseadas nos ligantes ou no alvo. No desenvolvimento de novos compostos, técnicas baseadas na estrutura, como o docking, podem ser aplicadas no estudo de um determinado receptor e seu respectivo ligante, avaliando as interações ligante-proteína. Ao passo que nos métodos baseados no ligante, um banco de ligantes conhecidos é utilizado, buscando modos de avaliar parâmetros (descritores moleculares) que possam auxiliar no desenvolvimento de compostos com maior potência. Este estudo teve como objetivo realizar estudos in silico para investigar interações fármaco-alvo com alcaloides oriundos de produtos naturais, e respectivos análogos, com relevante atividade farmacológica. Diferentes descritores moleculares e metodologias foram utilizadas nos estudos desenvolvidos. No capítulo 2, foi avaliado a interação do alcaloide bisindolico caulerpina (CLP) com a enzima envolvida na doença de Alzheimer (DA) monoamina oxidase B (MAO-B), além de um banco com 109 análogos. Foi possível observar um parâmetro químico de inibição dos análogos da CLP, onde a substituição dos radicais deve ser assimétrica com polaridade distinta. Os estudos dos baseados no ligante e na estrutura, associado à classificação drug-like, sugerem que o esqueleto químico da CLP tem potencial uso no tratamento da DA. No capítulo 3, 8 alcaloides isolados de Cissampelos sympodialis e 101 derivados, tiveram seu potencial inibitório contra enzimas (BACE, GSK-3β e MAO-A) envolvidas em doenças degenerativas avaliado por metodologias in silico. Análise consensual demonstrou afinidade de alcaloides bisbenzilisoquinolínicos pela BACE, incluindos os alcaloides naturais roraimina e simpodialina- β-N-oxide, suportando interesse em investigar este esqueleto como antagonista desta enzima. No capítulo 4 foi avaliado o potencial multi-target de 148 alcaloides aporfinicos de Annonaceae contra Leishmania donovani. Foram utilizadas seis enzimas desta doença negligenciada para o estudo teórico, que foi associado com dados experimentais de quatro alcaloides disponíveis e que integram o banco, que apresentaram valor pIC50 inferior a 5.26. O alcaloide xyloguyellina foi apontado como potencial agente multitarget, demonstrando atividade contra 5 das 6 enzimas avaliadas, com probabilidade de atividade superior a 60%. Descritores de fragmento foram utilizados para criar modelo baseado no ligante em uma abordagem paralela com docking molecular, para predizer a atividade citotóxica e contra topoisomerase II de azafenantreno alcaloides, no capítulo 5. A atividade citotóxica deste esqueleto de alcaloides está bem descrita na literatura, com diversas moléculas apresentando atividade contra linhagens de células tumorais. Os análogos IMB 6 e IMB 23 apresentaram interessante atividade e com seletividade, apresentando energia MolDock similar à liriodenina, composto caracterizado por potente ação antitumoral, porém com elevada toxicidade. Importantes informações estruturais são fornecidas pela espectroscopia de ressonância magnética nuclear (RMN), sendo o capítulo 6 destinado a discorrer sobre a importância desta técnica para geração de descritores moleculares. Estudos que aplicaram com sucesso descritores RMN em design de drogas assistida pelo computador encontram-se descritos, além de diversos estudos de QSAR e QSPR tendo como amparo dados de deslocamentos químicos.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-04-13T12:21:40Z No. of bitstreams: 1 viniciusschmitzpereiranunes.pdf: 31716642 bytes, checksum: 9cfc92a2078f124a8a9e3fa1c6509c7e (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-04-24T03:28:04Z (GMT) No. of bitstreams: 1 viniciusschmitzpereiranunes.pdf: 31716642 bytes, checksum: 9cfc92a2078f124a8a9e3fa1c6509c7e (MD5) / Made available in DSpace on 2016-04-24T03:28:04Z (GMT). No. of bitstreams: 1 viniciusschmitzpereiranunes.pdf: 31716642 bytes, checksum: 9cfc92a2078f124a8a9e3fa1c6509c7e (MD5) Previous issue date: 2015-12-07 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A Esquistossomose é uma doença negligenciada causada por parasitas do gênero Schistosoma. Segundo a Oganização Mundial da Saúde, mais de 200 milhões de pessoas no mundo estão infectadas, sendo de 4 a 6 milhões de pessoas somente no Brasil. A principal forma de tratamento da doença é o uso do medicamento praziquantel, porém, há relatos na literatura de resistência do parasita ao medicamento. Tal situação levantou a necessidade pela busca de novos alvos moleculares e novos medicamentos para o tratamento da doença. Um grupo de proteínas apresentadas como potenciais alvos moleculares de esquistomicidas é o das NTPDases. Estas enzimas hidrolisam nucleotídeos di e trifosfatados (e.g. ADP e ATP) em presença de cátions bivalentes, e estão descritas em diferentes organismos. No parasita Schistosoma mansoni foi descrita uma isoforma de NTPDase ancorada na membrana plasmática das células do tegumento do verme adulto e conhecida como SmATPDase1 ou Sm1. Segundo a literatura, esta isoforma é a segunda proteína mais expressa no tegumento dos vermes adultos. Devido à localização e a importância dos nucleotídeos di e trifosfatos na ativação hemostática e de células do sistema imunológico, foi sugerido que a Sm1 estaria envolvida na regulação das concentrações de nucleotídeos em torno do parasita, o que contribuiria com sua evasão. Baseado nos pressupostos acima, tem sido proposto o uso da Sm1 como possível alvo molecular de novos esquistomicidas. Nos mamíferos foram descritas oito isoformas de NTPDases. A isoforma 1 de humanos (HsNTPDase1), mais conhecida como CD39, está presente nas células do endotélio dos vasos sanguíneos, sendo responsável pela regulação das concentrações extracelulares de ATP e ADP. No presente trabalho, apresentamos os modelos 3D da Sm1 e CD39, construídos por meio da técnica de modelagem por homologia. Devido a semelhança da estrutura 3D de ambos os modelos, foi necessário realizar uma análise estrutural comparativa entre as duas enzimas, por meio de simulações de dinâmica molecular e estudos de docking receptor-ligante. Predição de cavidades foram feitas no modelo da Sm1 a fim de detectar cavidades diferentes do sítio-ativo que pudessem ser usadas em estudos de docking. Dessa etapa resultou a seleção de duas cavidades, o sítio-ativo e um sítio alternativo. Em seguida foram realizadas simulações de dinâmica molecular envolvendo os modelos da Sm1 e CD39, e os moldes PDB3ZX3 e PDB3CJA. Para cada modelo foram feitas duas simulações, uma com a presença do ANP (análogo do ATP) no sítio-ativo e uma na ausência do ANP. Em todas as quatro simulações os modelos estão acoplados a uma membrana do tipo POPC, e o tempo de simulação foi de 32ns. Para os moldes o tempo de simulação foi 40ns. As simulações mostraram que a região do sítio alternativo apresentou, no modelo da Sm1 sem o ligante, mudanças na conformação que não foram observadas na Sm1 com ligante e nas duas simulações envolvendo o modelo da CD39. Isso sugere que o ligante contribui na estabilização da estrutura da Sm1 e CD39. Também foram feitas análises de drogabilidade e de agrupamento das conformações geradas ao longo das simulações envolvendo os modelos. Para as análises de agrupamento foi proposto o uso da metodologia GLCM, juntamente com o algoritmo K-means. Essas análises tinham como objetivo selecionar conformações das trajetórias que pudessem ser usadas nos estudos de docking. Para os estudos de docking foram analisadas a afinidade de três ligantes (ANP, ARL67153 e praziquantel) no sítio ativo e no sítio alternativo, de ambas as enzimas. Para o sítio ativo, os melhores resultados foram obtidos com os ligantes ANP e ARL67153, em todas as simulações. Foi observado que o ARL67153 apresentou resultados similares com os do ANP. No sítio alternativo os melhores resultados foram obtidos com as conformações da simulação da Sm1 sem o ANP no sítio ativo, sendo que na CD39 nenhum dos ligantes foram atracados dentro do sítio. Com relação ao praziquantel, os melhores resultados foram observados no sítio ativo da Sm1 e CD39. É possível concluir que o sítio alternativo da Sm1 é uma região que pode ser usada para o atracamento de possíveis inibidores dessa enzima. / Schistosomiasis is a neglected disease caused by parasites of the genus Schistosoma. According to the World Health Organization, over 200 million people worldwide were infected, and 4 to 6 million people only in Brazil. The main treatment is the use of the drug praziquantel, but there are reports in the literature suggesting the parasite’s resistance to praziquantel. This situation raised the need for search new molecular targets and new drugs for treating this disease. A group of proteins as potential targets is NTPDase. These enzymes hydrolyse nucleotides (e.g., ADP and ATP) in the presence of bivalent cations, and they are described in different organisms. In the parasite Schistosoma mansoni, an isoform of NTPDase„ named SmATPDase1 or Sm1, was described as a protein anchored in the plasma membrane of cells in the seed coat of the adult worm. According to the literature, this isoform is the most expressed enzyme in the tegument of adult worms. Due to the location and importance of nucleotide triphosphates in the hemostatic and activation of immune cells, Sm1 has been suggested to be involved in the regulation of nucleotide concentrations around the parasite, which could be a mechanism of immune evasion in schistosomiasis. Based on the above assumptions, it has been proposed the use of Sm1 as a possible target for new schistosomicide drugs. In mammals have been described eight isoforms. Isoform 1 of human NTPDase (HsNTPDase1), also known as CD39, is present in the endothelial cells of blood vessels, and it is responsible for the regulation of extracellular concentrations of ATP and ADP. In this paper, we present 3D models of Sm1 and CD39, constructed by homology modeling technique. Due to the similarity of 3D structures of both models, it was necessary to perform a comparative structural analysis of both enzymes by molecular dynamics simulations and and receptorligand docking. Cavities prediction were made in Sm1’s model and two cavities were selected, the active site and an alternative binding site proposed in this work. After, it was performed molecular dynamics simulations involving models of Sm1 and CD39, and PDB3ZX3 and PDB3CJA templates. Two simulations were performed for each model, one in the presence of ANP (ATP analog) in the active-site and other in the absence. In models’ simulations, structures were coupled to a POPC membrane, and the simulation time was 32ns. Simulation time for templates was 40ns. Simulations showed that the alternative site in Sm1 without ANP presented conformational changes which were not observed in simulations of CD39 and Sm1 with ANP. This suggests that the presence of ligand in the active site contributes in stabilizing the structure of Sm1 and CD39. Druggability and clustering analysis were performed with conformations generated through simulations. In this work, we proposed the use of GLCM methodology with Kmeans algorithm for clustering analysis, aiming to select conformations from trajectories that could be used in receptor-ligand docking. We analyzed the affinity of three ligands (ANP, ARL67153 and praziquantel) in the active site and in the alternative site of Sm1 and CD39 enzymes. The best results for active site were obtained with ANP and ARL67153 ligands, in all simulations. For alternative site, the best results were obtained with conformations from the simulation of Sm1 without ANP in the active site. For CD39’s simulations, none of the ligands were docked within the cavity of alternative site. With regard to praziquantel, the best results were observed in the active site of Sm1 and CD39. It is possible to conclude that the alternative site of Sm1 is a region which can be used for docking of possible inhibitors of this enzyme.

Idag sker många transporter med låg utnyttjandegrad vilket gör att transportkostnaden per produkt blir hög samtidigt som transporter har en negativ påverkan på miljön. Genom att konsolidera transporter kan utnyttjandegraden av transporterna öka. Ökad utnyttjandegrad kan även hjälpa företagen att gå mot cirkulär ekonomi där målet är att utnyttja resurserna maximalt. För små och medelstora företag kan det dock vara svårt att bygga upp samarbeten med andra företag. Dessa företag möter olika möjligheter och hinder vid implementering av transportkonsolidering, därför kommer denna studien identifiera vilka dessa är. Studien har genomförts i samarbete med 16 företag i Orust kommun och har visat att de största hindren vid transportkonsolidering är kundkrav, produktkrav och informationsdelning. Företagen upplevde att kundernas krav på korta ledtider skulle göra det svårt att samordna transporter med andra företag. Många företag upplevde även att produktkraven deras produkter ställer på transporterna skulle försvåra transportkonsolidering. Studien kunde dock visa att flera företag hade liknande produktkrav vilket möjliggör transportkonsolidering. En del företag ansåg att det saknades stöd och samarbete för den informationsdelning som krävs vid konsolidering. De främsta möjligheterna som identifierades är företagskulturen och viljan att gå mot en mer hållbar distributionskedja. Företagen som deltog i intervjuerna nämnde att de såg positivt på transportkonsolidering om det fanns ett sätt att enkelt samordna transporterna. De är även aktiva i Orust Kretsloppsakademi som arbetar för ett hållbart Orust vilket visar att det finns ett intresse av att bli mer hållbara. / Today, many transports are at a low rate of utilization. This means that shipping costs per product will be high and at the same time transports have a negative impact on the environment. Consolidating transports can increase the utilization rate for transports which minimizes costs and environmental impact. Increased utilization rates can also help companies move towards circular economics where the goal is to maximize their utilization of resources. However, for small and medium size companies it may be difficult to build up partnerships with other companies. These companies face different possibilities and obstacles in implementing transport consolidation, therefore this study will identify these. The study has been carried out in cooperation with 16 companies in Orust and has shown that the main obstacles to transport consolidation are customer requirements, product requirements and information sharing. The companies perceived that customer demand for short lead times would make it difficult to coordinate transport with other companies. Many companies also found that the productrequirements of their products on transport would make transport consolidation difficult. However, the study showed that several companies had similar product requirements, which enables transport consolidation. Some companies also felt that there was no support and cooperation for the information sharing required for consolidation. The main opportunities identified were corporate culture and the desire to move towards a more sustainable distribution chain. The companies that participated in the interviews mentioned that they can see possibilities of transport consolidation if there was a way to easily coordinate transport. They are also active in the Orust Kretsloppsakademi that works for a sustainable Orust, which shows that there is an interest in becoming more sustainable.

Les hypersensibilités allergiques médicamenteuses sont des pathologies mettant en jeu le système immunitaire et induites par la prise de médicaments. Notre travail s’est décomposé en quatre étapes successives : 1- Nous avons classé les β-lactamines en fonction de leurs champs moléculaires, et obtenons un dendrogramme de 4 familles, validé par les données cliniques. Nous avons également réalisé une étude de 3D-QSAR visant à connaître les parties du médicament impliquées dans la pathologie, et à prédire l’allergénicité des β-lactamines. 2- Partant de l’hypothèse que les β-lactamines sont des haptènes, nous avons étudié leur réactivité vis-à-vis d’acides aminés de type lysine et sérine. Nous avons ensuite réalisé des expériences de « docking » afin de définir les interactions entre le médicament et l’albumine sérique humaine. Nous concluons que les sites des lysines 190 et 212 sont les plus adaptés pour la fixation covalente de la drogue et avons validé cette analyse par des méthodes mixtes QM/MM. Enfin, grâce à notre logiciel SuMo, nous avons déterminé d’autres protéines candidates pour l’hapténisation. 3- S’agissant des HyperSensibilités Allergiques Immédiates, nous avons modélisé les différents partenaires que sont les IgE, la β-lactamine portée ou non par une protéine. Nous avons envisagé plusieurs modes de reconnaissance. D’autre part, nous avons analysé les modifications de la protéine, induites par la fixation de la drogue. 4- Concernant les HSA retardées, nous avons émis plusieurs scénarios de reconnaissance de la β-lactamine par le TCR. Nous avons modélisé différents complexes impliquant le TCR, le peptide hapténisé par le médicament, un ion éventuel, ainsi que le CMH, et les soumettons à des dynamiques moléculaires afin d’en étudier la pertinence. D’autre part, nous avons déterminé plusieurs peptides, issus des protéines d’hapténisation et susceptibles de présenter le médicament au TCR, via le CMH. L’ensemble des résultats obtenus est ou sera validé par des expériences in vitro et in vivo. / Drug hypersensitivity is an immune-mediated reaction to a drug. Our work was divided into four stages: 1 - We have classified β-lactam antibiotics based on their molecular fields, and obtained a dendrogram of 4 families, validated by clinical data. We also conducted a 3D-QSAR study to determine what parts of the drug are involved in the pathology and to predict the allergenicity of β- lactams. 2 - Under the assumption that β-lactam antibiotics are haptens, we studied their reactivity in comparison with lysine and serine. We then conducted "docking" experiments to define the interactions between the drug and human serum albumin. We conclude that lysine 190 and 212 are the most suitable sites for the covalent binding of the drugs. We validate this analysis by mixed QM / MM methods. Finally, thanks to our software SuMo, we have found other candidate proteins for haptenization. 3 - Regarding immediate hypersensitivity reactions, we modeled the IgE, the β-lactam and the haptenized protein. We considered several modes of recognition. Secondly, we analyzed the structural changes of the protein induced by the binding of the drug. 4 - Concerning delayed reactions, we considered different scenarios for the recognition of β-lactam by the TCR. We modeled complexes involving the TCR, the peptide haptenized by the β-lactam, a possible ion, and the MHC. We investigated them with molecular dynamics to study their relevance. On the other hand, we have identified many peptides derived from haptenization proteins and able to present the drug to the TCR through the MHC. The validity of the obtained results is or will be confirmed using experiments in vitro and in vivo.

Afin d'apporter une aide pour la chimiotaxonomie du genre Stereocaulon, les acides gras totaux de dix espèces de Stéréocaulon, de quelques cyanolichens et d'une cyanobactérie ont été étudiés. Les profils obtenus des acides gras saturés, insaturés et ramifiés ont été comparés par classification hiérarchique ascendante. Les acides gras iso et antéiso pourraient permettre de distinguer le genre Stereocaulon des cyanolichens à la différence des autres classes d'acides gras. Dans un deuxième temps, l'étude phytochimique du lichen S. evolutum récolté en Bretagne a permis d'isoler et de caractériser 22 métabolites secondaires. Parmi ces composés, deux sont nouveaux. Sept molécules possèdent une structure proche de l'atranorine, depside abondant et récurrent chez les Stéréocaulons. L'atranorine ayant montré lors d'un criblage une activité intéressante sur le virus de l'hépatite C, six molécules ainsi que deux dérivés hémisynthétiques ont alors été évalués. L'atranorine et le 4-O-déméthylbarbatate de méthyle ont présenté une bonne activité anti-VHC, le premier ciblant l'étape de pénétration et le deuxième l'étape de réplication. D'autres composés, deux depsidones et cinq diphényléthers, ont été testés sur l'enzyme Protéine Tyrosine Phosphatase 1B (PTP1B) qui est une cible d'intétêt dans le traitement du diabète de type 2 et le cancer du sein. Les deux depsidones (acide lobarique, acide norlobarique) et un diphényléther, l'anhydro-sakisacaulon A, ont montré une inhibition de PTP1B avec des CI₅₀ similaires au témoin acide ursolique. La modélisation de cette enzyme ayant été réalisée en parallèle, les études de docking ont permis de proposer des mécanismes d'interactions mis en jeu lors de l'inhibition de PTP1B par ces métabolites secondaires lichéniques et d'envisager l'optimisation structurale de ces composés en vue d'augmenter leur activité. / Total fatty acids (FA) of ten species of Stereocaulon in addition to cyanolichens and one cyanobacterium were studied. FA profiles based on saturated-, unsaturated- and branched chain-FAs were compared using a hierarchical ascendant classification. Cyanolichens differed from the Stereocaulon genus according iso- and anteiso-FAs profiles while no differences were seen according the other FAs families. The phytochemical study of Stereocaulon evolutum, harvested in Brittany, led to isolation and identification of 22 secondary metabolites. Two were new for lichens. Among the isolated compounds, seven compounds were structurally close to atranorin, a common and abundant depside in the Stereocaulon genus. In a previous screening, atranorin exhibited a noteworthy HCV inhibition, thus six lichen compounds and two synthetic molecules were also tested. Atranorin and methyl 4-O-demethylbarbatate were the most potent without any cytotoxicity, the first being active towards the virus penetration and the latter against the virus replication. Two depsidones and five diphenylethers were also isolated and were evaluated on the Protein Tyrosine Phosphatase 1B (PTP1B), a promising target for type 2 mellitus diabetis and breast cancer. Both depsidones (lobaric acid, norlobaric acid) and the diphenylether anhydrosakisacaulon A were as potent as the positive control ursolic acid. Simultaneously, a molecular docking study between PTP1B and the seven compounds suggested the most significant interactions to conceive possible more active compounds.

Les travaux de cette thèse ont porté sur le développement de deux méthodes de modélisation des enzymes contenant des groupes prosthétiques de la famille des flavines.La première méthode, PredFace, permet de prédire la stéréochimie des produits d'une réaction catalysée par des enzymes contenant des groupes prosthétiques, en identifiant la face libre d'interaction avec les substrats. Le protocole mis en place pour cette méthode implique l'utilisation de huit complexes "sondes", obtenus par des opérations de symétrie à partir de l'état de transition de la réaction de transfert d'un atome d'hydrogène entre le nicotinamide et la lumiflavine. Ces complexes sont positionnés dans le site actif avec le groupe prosthétique comme référence et dans chaque cas l'énergie d'interaction protéine-ligand est évaluée par la fonction de score implémentée dans le logiciel de docking utilisé (AutoDock). L'énergie d'interaction la plus favorable permet d'identifier la face du groupe prosthétique accessible pour la réaction enzymatique dans le site actif. La méthode PredFace a été validée par l'analyse de l'ensemble des structures de la Protein Data Bank contenant des groupes prosthétiques de la famille des flavines (2170). Le protocole mis au point est très rapide (moins d'une minute), ce qui nous a permis de développer un site web afin de mettre cette méthode à la disposition de la communauté.La seconde méthode, ProsthDock, est une nouvelle méthode de docking basée sur le mécanisme d'une réaction enzymatique catalysée par un groupe prosthétique et guidée par la présence de ce groupe prosthétique dans le site actif de l'enzyme. Le développement de cette méthode a été motivé par le fait que les méthodes actuelles de docking, en présence de groupes prosthétiques, se révèlent incapables de produire des poses correctes pour des substrats, en accord avec les réactions enzymatiques. Afin de remédier à ce problème nous avons ajouté à la fonction de score classique un terme supplémentaire, qui rendra compte de l'interaction du ligand avec le groupe prosthétique. Dans un premier temps, nous avons construit un modèle simplifié du complexe NADH/FMN et calculé l'état de transition de la réaction de transfert d'hydrogène entre les deux partenaires. Des surfaces d'énergie potentielle pour cette réaction ont été calculées en variant la distance, l'angle et l'angle dièdre entre les deux réactifs. Un docking sous contrainte est ensuite réalisé et en fonction du positionnement de chaque pose de docking dans le site actif le terme supplémentaire de la fonction de score est calculé à partir des surfaces d'énergie potentielle, ce qui nous permet de modifier le classement des résultats de docking en favorisant les poses qui sont en accord avec la réaction enzymatique. / During this PhD thesis we developped two new molecular modeling methods applied to enzymes containing flavin-type prosthetic groups.The first method, PredFace, predicts the stereochemistry of products from a reaction catalyzed by enzymes containing prosthetic groups, by automatically identifying the solvent-exposed face of the prosthetic group. The protocol involves the use of eigth complexes as "probes", obtained by symmetry operations starting from the transition state of a hydrogen atom transfer reaction between nicotinamide and lumiflavin. These complexes are positioned in the binding site with the prosthetic group as reference and the energy of the protein-ligand interaction is evaluated by the scoring function implemented in the docking software (AutoDock). The most favorable interaction energy allows the identification of the prosthetic group face that is available for the enzymatic reaction in the binding site. The PredFace method has been validated by analyzing all the structures in the Protein Data Bank containing flavin-derived prosthetic groups (2170). This method is very fast (less than a minute), which allowed us to develop a web site open to the scientific community.The second method, ProsthDock, is a new mechanism-based molecular docking method guided by prosthetic groups present in the active sites of enzymes. The development of this method was motivated by the incapacity of the currently available docking methods to provide, in the presence of prosthetic groups, ligand conformations that are compatible with the enzymatic reactions. In this regard, we have added a new term to the classical scoring function, to take into account the interaction between ligand and prosthetic group. We have built a simplified model of the NADH/FMN complex and calculated the transition state of the hydrogen transfer reaction between the two partners. Potential energy surfaces have been calculated for this reaction by variating the angle, diedral angle and distance between the two reaction partners. A subsequent docking with constraints provides binding site conformations of the ligand for which the new term of the scoring function is calculated using the potential energy surfaces. This results in a new ranking of the docking poses, favoring those in agreement with the enzymatic reaction.

Photosystem I (PSI) aus dem thermophilen Cyanobakterium Thermosynechococcus elongatus ist ein transmembraner Protein-Pigment-Superkomplex der photosynthetischen Elektronentransportkette. Er wandelt die Energie des Lichts in elektrische Energie mit einer Quanteneffizienz von nahezu 100 % um. Dazu uberträgt PSI Elektronen von Plastocyanin bzw. Cytochrom c6 (Cyt c6) auf Ferredoxin. Die Struktur des PSI wurde bereits 2001 mit einer Auflösung von 2,5 Å beschrieben (Jordan et al. 2001). Es lässt sich zur Generierung von Photoströmen auf Elektrodenoberflächen assemblieren und zur Produktion von Biokraftstoffen mit Enzymen koppeln. Die elektrische Kontaktierung des PSI mit Elektrodenoberflächen kann durch Komplexierung mit dem mitochondrialem Cytochrom c aus Pferdeherz (Cyt cHH) erhöht werden. Aufgrund der Nutzbarkeit dieses Proteinkomplexes sollte geklärt werden, wie PSI und Cyt cHH wechselwirken und wie sich die Interaktion von der des nativen PSI-Cyt c6-Komplexes unterscheidet. Deshalb lag der Fokus meiner Arbeit darauf, die Bindung des Cyt c6 und seines Analogons Cyt cHH an PSI mit kinetischen, kalorimetrischen, theoretischen und strukturellen Methoden zu untersuchen. Das Cyt c6 bindet im reduzierten Zustand an PSI und verringert nach erfolgtem Elektronentransfer seine Affinität. Das Cyt cHH bindet dagegen sowohl im reduzierten als auch im oxidierten Zustand an PSI. Mit Hilfe der kinetischen Messungen habe ich Bedingungen identifiziert, unter denen PSI mit dem jeweiligen Cytochrom c einen stabilen Komplex eingeht. Mit Hilfe eines rigid-body dockings wurden potenzielle Bindungsstellen der beiden Cytochrome berechnet. Fur Cyt c6 ergab sich eine spezifische Bindungsstelle, die eine gute Übereinstimmung mit den von mir gemessenen Kinetiken sowie mit weiteren Literaturdaten zeigt. Diese Bindungsstelle korreliert mit der veröffentlichten Kostruktur des bakteriellen Reaktionszentrums mit Cyt c2 aus Rhodobacter sphaeroides. Demgegenüber sind mehrere Cyt cHH-Bindungsstellen ... / Photosystem I (PSI) from the thermophilic cyanobacterium Thermosynechococcus elongatus is a membrane-bound, multipigment protein supercomplex. It converts light to electrochemical energy with a quantum efficiency of almost 100 %. It reduces the luminal proteins plastocyanin and cytochrome c6 (Cyt c6) to oxidize the stromal protein Ferredoxin. The structure of PSI has been solved in 2001 at a resolution of 2,5 Å (Jordan et al. 2001). PSI can be assembled on an electrode surface to produce photocurrents and the generated electrons can be used for the production of biofuels. The mitochondrial cytochrome c from horse heart (Cyt cHH) binds strongly to both, PSI and the electrode surface, and can therefore be applied to improve the electrical coupling. Due to the practical use of the PSI-Cyt c complex, the aim of my thesis is to characterize the interaction of PSI with Cyt c6 and the analog Cyt cHH. To this end, the binding of both cytochromes to PSI was analyzed by kinetic, calorimetric, theory-based and structural methods. Cyt c6 binds to PSI while being reduced and decreases its affinity after transferring its electron. In contrast, Cyt cHH binds to PSI in both oxidation states, reduced and oxidized, with identical affinity. By means of kinetic measurements, I identified conditions in which PSI forms a stable complex with either of the two cytochromes. The positions of the cytochrome binding sites at PSI were calculated by a rigid-body docking. For the calculation with Cyt c6, the majority of the potential binding sites are located at the luminal side of PSI, close to P700. The theoretic properties of one of these binding sites are in good agreement with my own kinetic measurements and literature data. The position and orientation of Cyt c6 in this theoretic binding site is almost identical to the localization of Cyt c2 in cocrystals with the bacterial reaction center from Rhodobacter sphaeroides. The potential Cyt cHH binding sites are uniformly distributed over ...

På en alltmer global handelsplats med allt tuffare kundkrav handskas många företag med utmaningar kopplade till flexibilitet. Kunderna vill ha korta ledtider, stora anpassningsmöjligheter och utmärkt service, naturligtvis till ett lågt pris. Ytterligare en dimension av komplexitet adderas när stora koncerner gör förvärv av mindre bolag, vilket gör att koncernen måste säkerställa att även dessa nya förvärv kan möta kundens krav i samma utsträckning.  En lösning på denna problematik återfinns i litteraturen i konceptet logistikplattform. Konceptet innebär att ett företag arbetar med en centralt framtagen resursbas som sedan servar alla delar av företaget på en mer decentraliserad nivå för att kunna möta kundens krav. Fem viktiga byggstenar i en logistikplattform är central styrning, logistiska koncept, fysisk struktur, logistiska processer och aktiviteter samt informationssystem (Abrahamsson, et al., 2003).  I denna studie beskrivs koncernen Kesko, som i Sverige framför allt är aktiv inom byggbranschen och den tekniska handeln, med varumärkena K-Bygg, K-Rauta, Onninen samt Mark & Infra. Där återfinns denna problematik, speciellt kopplat till förvärv och kapaciteten på centrallagret som servar hela koncernen. Baserat på detta har denna studie syftet att utreda hur Kesko kan använda sig av en logistikplattform för att serva de olika varumärkena samt vad användandet får för konsekvens för centrallagret i Pilängen.  Studien fokuserar framförallt på de logistiska koncepten och den fysiska strukturen inom Kesko. De logistiska koncepten har avgränsats till att handla om försörjningskoncepten lagerhållning, kontinuerlig försörjning, leverantörsstyrt lager, cross-docking samt direktleverans och den fysiska strukturen har avgränsats till att hantera lokaliseringsstrategi, lagerstrategi samt transportstrategi.  Baserat på Keskos kunders, leverantörers samt produkters karaktäristik utformas vilka krav detta ställer på en logistikplattformen. Baserat på denna karaktäristik och krav utreds en ideal bild av Keskos logistikplattform i form av försörjningskoncept och den fysiska strukturen. Sedan utreds hur Kesko i nuläget verkligen arbetar med försörjningskoncepten och den fysiska strukturen. Dessa två versioner, den ideala bilden och nuläget, jämförs sedan i en så kallad gap-analys där skillnader utreds för att upptäcka var förbättringspotential finns och vilka förändringar Kesko kan genomföra för att kunna sägas jobba mot konceptet logistikplattform.  Analysen visar att Kesko är på god väg till det som anses viktigt inom konceptet, men att framtiden ställer stora krav på centrallagret och dess kapacitet. De sex gap som identifierades mellan den ideala och nuvarande utformningen och som ansågs påverka kapaciteten på centrallagret var 1) Användandet av cross-docking, 2) E-handelslagrets lokalisering och transportupplägg, 3) Förädlingsstrukturen, 4) Varumärket K-Byggs sortiment på centrallagret, 5) Varumärket Onninens sortiment på centrallagret och 6) Användandet av extern part för säsongslagring. Utifrån dessa gap formulerades åtta stycken förändringsförslag för hur Kesko kan minimera dessa gap och i och med detta gå mot den mer ideala utformningen. Förslagen visade att centrallagret, för att kunna fungera som en resursbas för Kesko i framtiden, troligen behöver en utökning av antalet pallplatser och plockautomatsplatser, en utökning av antalet in- och utlastningsportar samt utlastningsyta. Genom dessa förändringar förväntas centrallagret bli bättre anpassat för att serva de nuvarande varumärkena inom koncernen men även vara bättre förberett för att serva framtida nyförvärv. / In a business environment which is becoming more and more globalized and with continually increasing customer requirements, companies are dealing with flexibility challenges. Customers want short lead times, a lot of customization and excellent service, everything while keeping prices low. Another dimension of complexity is added when large company groups make acquisitions of smaller companies, which means that the company group must ensure that these new acquisitions also can meet the customer's requirements to the same extent.  A solution to this problem can be found in the literature as the concept of a logistics platform. The concept describes a company working with a centralized resource base that serves all parts of the company at a decentralized level in order to meet the customer's requirements. Five building blocks of a logistics platform are central control, logistics concepts, physical structure, logistics processes and activities, and information systems (Abrahamsson, et al., 2003)  This study describes Kesko Sverige, which is a company primarily active in the construction and technical trade, with the brands K-Bygg, K-Rauta, Onninen and Mark & Infra. The problems described above are also found within Kesko, especially regarding acquisitions and the capacity of the central warehouse, which is a warehouse that serves all brands in Kesko Sverige. Therefore, the purpose of this study is to investigate how Kesko can use a logistics platform to serve the various brands and what the use is for the central warehouse in Pilängen.  The study primarily focuses on the logistical concepts and the physical structures within Kesko. The logistics concepts have been restricted to deal with the distribution concepts warehousing, continuous replenishment, vendor managed inventory, cross-docking and direct deliveries, and the physical structure has been restricted to handle location strategy, inventory strategy and transport strategy.  Based on Kesko's customer, supplier and product characteristics, the requirements for the logistics platform are discovered. Based on these characteristics and requirements, an ideal picture of Kesko's logistics platform in the form of distribution concepts and the physical structure is investigated. It is then investigated how Kesko currently is applying the distribution concepts and the physical structure. These two versions, the ideal state and the current state, are then compared in a so-called gap analysis where differences are investigated to discover where there are areas for improvement for Kesko to be considered working towards the concept of a logistics platform.  The analysis shows that Kesko is well on its way to what is considered important in the concept, but that the future places great demand on the central warehouse and its capacity. The 6 gaps that were identified between the ideal and current state and which were considered to affect the capacity of the central warehouse were 1) The use of cross-docking, 2) The e-commerce location and transport arrangements, 3) The physical structure for value-adding services, 4) K-Bygg's assortment at the central warehouse, 5) Onninen's assortment at the central warehouse and 6) The use of external part for seasonal storage. Based on these gaps, eight proposals were formulated regarding how Kesko can minimize these gaps and hence move towards the ideal state. The proposals showed that the central warehouse, in order to work as a resource base for Kesko in the future, probably needs an increase in the number of pallets and places in the automated picking machine, as well as an increased number of loading and unloading ports and an expansion of the unloading area. By making these changes the central warehouse will be better at serving the current brands and the warehouse will also be better prepared to serve future acquisitions.