TRAIL (TNF-related apoptosis inducing ligand) est une protéine anti-tumorale capable de se lier spécifiquement aux récepteurs agonistes de mort (TRAIL-Rl ou DR4 et TRAIL-R2 ou DR5) des cellules cancéreuses et d'induire leur apoptose sans être toxique pour les cellules saines. Grâce à leurs propriétés exceptionnelles, notamment leur biocompatibilité, les nanotubes de carbone et surtout les SWCNTSs sont utilisés dans un large éventail d'applications et sont considérés très prometteurs pour révolutionner la thérapie anticancéreuse en nanomédecine. Les SWCNTSs sont connus par leur diffusion rapide dans un milieu aqueux tel que le sang, ouvrant la voie de développement de nouveaux nanovecteurs de médicaments. L'objectif principal de nos travaux de thèse a consisté à fonctionnaliser TRAIL sur des SWCNTSs pour mimer sa fonction membranaire en induisant une forte agrégation des récepteurs et déclencher l'apoptose (mort cellulaire programmée). Dans un premier temps, la fonctionnalisation des SWCNTSs avec TRAIL a été réalisée: adsorption non covalente des molécules de PSE sur les nanotubes via 1t-1t stacking, puis greffage du TRAIL au complexe SWCNTS-PSE pour former le nanovecteur (nommé NPT). Ensuite, nous avons caractérisé notre NPT par différentes méthodes (RAMAN, XPS, IR, MET, STEM ... ) afin d'estimer le taux de greffage du TRAIL sur le NPT, qui était environ de 80%. Dans un deuxième temps, nous avons étudié les paramètres thermodynamiques tels que le pH et la température du NPT en comparaison avec TRAIL seul par une approche chromatographique d'affinité (CHLP). Les résultats obtenus montrent une meilleure affinité du nanovecteur par rapport à TRAIL seul avec le récepteur TRAIL-R2 immobilisé sur la colonne chromatographique. En outre, des calculs de docking ont montré également que le complexe NPT couplé aux homotrimères de TRAIL est le plus stable une fois docké au récepteur TRAIL-R2. Ainsi, nous avons montré que les interactions de type Van der Waals et des liaisons hydrogène régissent l'association NPT-DR5 pour un pH supérieur à 7,4 (comme pour TRAIL seul). Enfin, notre nanovecteur s'est avéré plus efficace que TRAIL seul dans des différents tests menés in vitro sur des plusieurs types de lignées tumorales. Le NPT a permis une augmentation du potentiel pro­apoptotique de TRAIL avec un gain de fonction apoptotique estimé entre 10-20 fois par rapport à celui obtenu avec TRAIL seul. Dans ce travail, nous fournissons ainsi une preuve de concept que les nanovecteurs basés sur la fonctionnalisation du TRAIL avec les SWCNTSs peuvent être utiles pour les futurs traitements anti-cancéreux en nanomédecine. / TRAIL (TNF-related apoptosis inducing ligand) is a protein involved in immune anti-tumor surveillance. This cytokine is able to bound specifically to agonist death receptors (TRAIL-Rl or DR4 and TRAIL-R2 or DR5) of cancer cells, inducing apoptosis without being taxie to healthy cells. Thanks to their exceptional properties such as biocompatibility, carbon nanotubes and especially single-walled carbon nanotubes (SWCNTSs) are used in a wide range of applications and are considered to be very promising for cancer therapy in nanomedicine. The SWCNTSs are known to rapidly diffuse in aqueous media such as blood, opening the way for the development of new drug nanovectors or nanocarriers. The main purpose of this work is to functionalize SWCNTSs with TRAIL to mimic the membrane function of TRAIL by inducing a strong aggregation of death receptors and then induce apoptosis. First of all, the choice of SWCNTS functionalization with TRAIL was considered the first key in this thesis: non-covalent adsorption of PSE molecules on the nanotubes via 1t-1t stacking and TRAIL was next attached to a SWCNTS-PSE to form our nanovector, called NPT. Then, the NPT was characterized by various methods (Raman, XPS, IR, TEM, STEM, ... ) in order to estimate the grafted degree of TRAIL on the NPT surface (about 80%). Secondly, we investigated the ef:fects of the thermodynamic parameters such as pH and temperature on NPT versus TRAIL by a chromatographie approach (HPLC). The results showed a better affinity for NPT compared to TRAIL alone with the TRAIL-R2 receptor immobilized on the chromatographie colurnn. In addition, docking calculations have also shown that the NPT complex coupled to TRAIL homotrimers is the most stable when docked to DR5. Thus, we have demonstrated that Van der Waals interactions and hydrogen bonds govem the NPT-DR5 association for pH > 7.4 (as for TRAIL). Finally, our TRAIL-based SWCNTSs nanovectors (NPT) proved to be more efficient than TRAIL alone towards death receptors in triggering cancer cell killing in vitro. These NPTs increased the pro-apoptotic potential of TRAIL by nearly 10 to 20-fold in different Human tumor cell lines tested including colorectal, non-small cell lung cancer, or hepatocarcinomas. We provide in this work a proof of concept that nanovectors based on SWCNTS functionalization with TRAIL may be useful for future cancer treatments in nanomedicine.

Les lactones macrocycliques (LM) sont des anthelminthiques (AH) à effet paralysant très utilisés chez les animaux et les humains contre les nématodes parasites. Cependant, leur succès thérapeutique est compromis par la résistance croissante aux LM, qui pourrait être en partie dû aux ABC transporteurs P-glycoprotéines (Pgps) sélectionnés et surexprimés chez les nématodes résistants aux LM. Dans ce travail, nous avons étudié plus précisément la P-glycoprotéine 13 du parasite de petits ruminants, Haemonchus contortus. Son orthologue chez le modèle nématode C. elegans, Cel-Pgp-13, est exprimé dans les amphides, structures qui ont été associées à la sensibilité aux AH chez C. elegans et H. contortus. Pour prédire la capacité des Pgps de nematode à transporter des drogues, incluant des LM et autres AH, nous avons développé un modèle de docking in silico. Nous avons utilisé la structure cristallographique de C. elegans Pgp-1 (Cel-Pgp-1), et nous avons montré la liaison avec une forte affinité de plusieurs ligands décrits comme activateurs de sa fonction ATPasique. Nous avons aussi décrit une forte affinité des LM, et un site spécifique de liaison de ces composés à Cel-Pgp-1. Cette approche représente un outil important pour prédire les interactions entre AH, et pour concevoir rationnellement de nouveaux inhibiteurs compétitifs des Pgps de nématode, dans le but d'améliorer les stratégies thérapeutiques. Sur la base de cette approche, nous avons prédit la structure 3D de Hco-Pgp-13 à partir du cristal de Cel-Pgp-1 afin d'étudier son intéraction avec des substrats potentiels, en particulier les LM. Nous avons trouvé des affinités similaires pour différents composés précédemment testés sur Cel-Pgp-1. In vitro, la mesure de l'activité ATPasique montre que l'actinomycine D est un substrat de Hco-Pgp-13. Nos données démontrent la présence possible d'un domaine de reconnaissance multispécifique sur ce transporteur de parasite. La détermination par immunofluorescence de l'expression de Hco-Pgp-13 a montré une distribution tissulaire large indiquant que Hco-Pgp-13 pourrait jouer un role important dans le transport de substrats endogènes et/ou exogènes. En conclusion, ce travail permet de mieux comprendre le rôle des Pgps de nématodes dans le transport de médicaments AH, tant au niveau de l'organisme modèle C. elegans que du nématode parasite H. contortus. Cette étude suggère la conservation de la fonction de tranporteur ABC multidrogue dans ces espèces. La localisation de Hco-Pgp-13 sur les structures amphidiales, et son éventuelle implication dans la résistance aux médicaments et à la survie de H. contortus à l'exposition à des composés AH, restent à préciser. / Macrocyclic lactones (ML) are paralyzing anthelmintics used in animals and humans against parasite nematodes. However, their therapeutic success is compromised by the spread of ML resistance. This might be at least partly due to P-glycoproteins (Pgps) ABC transporters that are selected and overexpressed in ML-resistant nematodes. Deciphering the role of the 10 Pgps expressed in the parasite of small ruminants Haemonchus contortus is thus of major importance to guaranty anthelmintic (AH) efficacy of various drugs. Here we focused on Hco-Pgp-13 due to the expression in the amphids of its closest ortholog in the model nematode C. elegans. Indeed, the amphids represent a putative entry route of drugs to reach AH targets in the nervous system and have been linked to AH susceptibility in C. elegans and H. contortus. In order to predict the capacity of nematode Pgps to transport drugs, including ML and otherAH, we have developed an in silico drug docking model. We have used C. elegans Pgp-1 (Cel-Pgp-1) crystal structure and have showed a high affinity binding of several ligands that have been shown to be activators of its ATPase function. ML were also found to bind with high affinity to Cel-Pgp-1, on a specific binding site. This approach provides a valuable tool to predict drug-drug interactions and to rationally design new competitive inhibitors of nematode Pgps, in order to improve anthelmintic therapeutics. We then predicted a putative 3D structure of Hco-Pgp-13 based on the recently released crystal of Cel-Pgp-1, with which it presented a high homology. This allowed the study of the interaction of Hco-Pgp-13 with potential substrates, in particular ML. We found similar affinities for various drugs previously tested on Cel-Pgp-1, supporting the good homology of these two proteins. Together with in vitro ATPase assay experiments that confirmed the substrate status of actinomycin D, this indicates a possible multispecifc recognition capacity of this parasitic transporter. The determination of Hco-Pgp-13 localization using immunohistochemistry showed a wide tissue expression consistent with a critical role for Hco-Pgp-13 in endogenous and/or exogenous substrate transport. In conclusion, this work provides insights into the role of nematode Pgps in transporting AH drugs, both at the level of the model organism C. elegans and of the parasitic nematode H. contortus. This suggests a high homology of function conserved between ABC tranporters in these species. The localization of such protein on amphidial structures and its possible involvement in drug resistance and survival of H. contortus to exposure to AH compounds remain to be precised.

<p dir="ltr">The growing movement toward sustainable use of ocean resources is driven by the pressing need to alleviate environmental and human stressors on the planet and its oceans. From monitoring the food web to supporting sustainable fisheries and observing environmental shifts to protect against the effects of climate change, ocean observations significantly impact the Blue Economy. Acknowledging the critical role of Autonomous Underwater Vehicles (AUVs) in achieving persistent ocean exploration, this research addresses challenges focusing on the limited energy and storage capacity of AUVs, introducing a comprehensive underwater docking solution with a specific emphasis on enhancing the terminal homing phase through innovative vision algorithms leveraging neural networks.</p><p dir="ltr">The primary goal of this work is to establish a docking procedure that is failure-tolerant, scalable, and systematically validated across diverse environmental conditions. To fulfill this objective, a robust dock detection mechanism has been developed that ensures the resilience of the docking procedure through \comment{an} improved detection in different challenging environmental conditions. Additionally, the study addresses the prevalent issue of data sparsity in the marine domain by artificially generating data using CycleGAN and Artistic Style Transfer. These approaches effectively provide sufficient data for the docking detection algorithm, improving the localization of the docking station.</p><p dir="ltr">Furthermore, this work introduces methods to compress the learned docking detection model without compromising performance, enhancing the efficiency of the overall system. Alongside these advancements, a station-keeping algorithm is presented, enabling the mobile docking station to maintain position and heading while awaiting the arrival of the AUV. To leverage the sensors onboard and to take advantage of the computational resources to their fullest extent, this research has demonstrated the feasibility of simultaneously learning docking detection and marine wildlife classification through multi-task and transfer learning. This multifaceted approach not only tackles the limitations of AUVs' energy and storage capacity but also contributes to the robustness, scalability, and systematic validation of underwater docking procedures, aligning with the broader goals of sustainable ocean exploration and the blue economy.</p>

SIRT1 and SIRT2 are two NAD⁺-dependent deacetylases which negatively modulate the activity of p53, a protein which is involved in cell cycle arrest, senescence and apoptosis following genotoxic stress. Part I of the thesis describes the exploration of the chemical space around a reported unselective and modest inhibitor of SIRT1 and SIRT2 with the aim of improving the selectivity and potency of the inhibitor against the two isoforms. Particular emphasis is placed upon understanding the mode of binding of the novel analogues within the active site of the enzymes. Chapter 1 reviews the physiological roles of class III NAD⁺-dependent deacetylases, also known as sirtuins. In particular, the application of SIRT1 and SIRT2 inhibitors as potential anticancer agents is described. Amongst these, only cambinol and the tenovins showed in vivo activity in a mouse xenograft model. Previously only one analogue of cambinol had been reported in the literature. Chapter 2 describes the development of a small collection of novel cambinol analogues (First Generation Studies). The role played by different substituents at the phenyl group and at the N-1 of the thiouracil core is discussed. Along with the synthesis and structure activity relationship (SAR) associated with the core structure, in-cell experiments intended to confirm the activity of the most active compounds are reported. Chapter 3 provides a rationalisation for the SAR discussed in Chapter 2. Based on computational molecular modelling studies (GOLD), the activity of the most potent and selective SIRT2 inhibitors is explained. Two series of novel cambinol analogues were designed (Second and Third Generation Analogues) in order to assess further the proposed binding mode. Chapter 4 focuses on the development of the “Second Generation” analogues, characterised by the presence of lipophilic substituents at the sulfur atom and at the N-3 position of the thiouracil core. The synthesis, biological evaluation and SAR are discussed in detail. Chapter 5 reports the development of the “Third Generation” analogues, characterised by either a benzyl group or para-alkoxy-substituted benzyl group at the N-1 position of cambinol. Once again, the synthesis, biological evaluation and SAR data are presented. An improved understanding of the mode of binding of the novel compounds is proposed based on molecular dynamics (MD) studies. Indole-based alkaloids, such as Vincristine and Vinblastine, are well known for their anticancer activity. Recently, the anticancer activity of members of the calycanthaceous family of alkaloids has been discovered. Part II of the thesis focuses on model studies aimed at developing the total synthesis of one of these compounds, perophoramidine. Chapter 7 provides an overview of the calycanthaceous alkaloid family of natural products, including their biological properties. The structural features of perophoramidine, along with the previously reported synthetic studies are outlined. Chapter 8 describes the synthesis of an advanced intermediate in the total synthesis of dehaloperophoramidine, a structural analogue of perophoramidine Problems encountered, optimisation studies and the synthesis of a re-designed intermediate are also reported in this chapter.

Attitude and position determination systems in satellites are absolutely necessary to keep the desired trajectory. A very accurate, reliable and most used sensor for attitude determination is the star tracker, which orient itself in space by observing and comparing star constellations with known star patterns. For on earth tests of movements and docking maneuvers of spacecrafts, the new Spacecraft Maneuvering and Docking (SMD) facility at the chair of Aerospace Information Technology at the University of Würzburg has been built. Air bearing systems on the space ve- hicles help to create micro gravity environment on a smooth surface and simulate an artificial space-like surrounding. A new star tracker based optical sensor for indoor application need to be developed in order to get the attitude and position of the vehicles. The main objective of this thesis is to research on feasible star tracking algorithms for the SMD facility first and later to implement a star detection software framework with new developed voting methods to give the star tracker system its fully autonomous function of attitude determination and position tracking. Furthermore, together with image processing techniques, the software framework is embedded into a controller board. This thesis proposes also a wireless network system for the facility, where all the devices on the vehicles can uniquely communicate within the same network and a devel- opment of a ground station to monitor the star tracker process has also been introduced. Multiple test results with different scenarios on position tracking and attitude determination, discussions and suggestions on improvements complete the entire thesis work.

Computational methods, including homology modelling, in-silico dockings, and molecular dynamics simulations have been used to study the functional dynamics and interactions of K⁺ channels. Molecular models were built of the inwardly rectifying K⁺ channel Kir2.2, the bacterial homolog K⁺ channel KirBac3.1, and the twin pore (K2P) K⁺ channels TREK-1 and TRESK. To investigate the electrostatic energy profile of K⁺ permeating through these homology models, continuum electrostatic calculations were performed. The primary mechanism of KirBac3.1 gating is believed to involve an opening at the helix bundle crossing (HBC). However, simulations of Kir channels have not yet revealed opening at the HBC. Here, in simulations of the new KirBac3.1-S129R X-ray crystal structure, in which the HBC was trapped open by the S129R mutation in the inner pore-lining helix (TM2), the HBC was found to exhibit considerable mobility. In a simulation of the new KirBac3.1-S129R-S205L double mutant structure, if the S129R and the S205L mutations were converted back to the wild-type serine, the HBC would close faster than in the simulations of the KirBac3.1-S129R single mutant structure. The double mutant structure KirBac3.1-S129R-S205L therefore likely represents a higher-energy state than the single mutant KirBac3.1-S129R structure, and these simulations indicate a staged pathway of gating in KirBac channels. Molecular modelling and MD simulations of the Kir2.2 channel structure demonstrated that the HBC would tend to open if the C-linker between the transmembrane and cytoplasmic domain was modelled helical. The electrostatic energy barrier for K⁺ permeation at the helix bundle crossing was found to be sensitive to subtle structural changes in the C-linker. Charge neutralization or charge reversal of the PIP2-binding residue R186 on the C-linker decreased the electrostatic barrier for K⁺ permeation through the HBC, suggesting an electrostatic contribution to the PIP2-dependent gating mechanism. Multi-scale simulations determined the PIP2 binding site in Kir2.2, in good agreement with crystallographic predictions. A TREK-1 homology model was built, based on the TRAAK structure. Two PIP2 binding sites were found in this TREK-1 model, at the C-terminal end, in line with existing functional data, and between transmembrane helices TM2 and TM3. The TM2-TM3 site is in reasonably good agreement with electron density attributed to an acyl tail in a recently deposited TREK-2 structure.

No description available.

Submitted by Caroline Xavier (caroline.xavier@pucrs.br) on 2017-06-05T14:58:52Z No. of bitstreams: 1 TES_RENATA_DE_PARIS_COMPLETO.pdf: 8873897 bytes, checksum: 43b2a883518fc9ce39978e816042ab5f (MD5) / Made available in DSpace on 2017-06-05T14:58:53Z (GMT). No. of bitstreams: 1 TES_RENATA_DE_PARIS_COMPLETO.pdf: 8873897 bytes, checksum: 43b2a883518fc9ce39978e816042ab5f (MD5) Previous issue date: 2016-10-28 / Conselho Nacional de Pesquisa e Desenvolvimento Cient?fico e Tecnol?gico - CNPq / O uso de conforma??es obtidas por trajet?rias da din?mica molecular nos experimentos de docagem molecular ? a abordagem mais precisa para simular o comportamento de receptores e ligantes em ambientes moleculares. Entretanto, tais simula??es exigem alto custo computacional e a sua completa execu??o pode se tornar uma tarefa impratic?vel devido ao vasto n?mero de informa??es estruturais consideradas para representar a expl?cita flexibilidade de receptores. Al?m disso, o problema ? ainda mais desafiante quando deseja-se utilizar modelos de receptores totalmente flex?veis (Fully-Flexible Receptor - FFR) para realizar a triagem virtual em bibliotecas de ligantes. Este estudo apresenta um m?todo inovador para otimizar a triagem virtual baseada em docagem molecular de modelos FFR por meio da redu??o do n?mero de experimentos de docagem e, da invoca??o escalar de workflows de docagem para m?quinas virtuais de plataformas em nuvem. Para esse prop?sito, o workflow cient?fico basedo em nuvem, chamado e-FReDock, foi desenvolvido para acelerar as simula??es da docagem molecular em larga escala. e-FReDock ? baseado em um m?todo seletivo sem param?tros para executar experimentos de docagem ensemble com m?ltiplos ligantes. Como dados de entrada do e-FReDock, aplicou-se seis m?todos de agrupamento para particionar conforma??es com diferentes caracter?sticas estruturais no s?tio de liga??o da cavidade do substrato do receptor, visando identificar grupos de conforma??es favor?veis a interagir com espec?ficos ligantes durante os experimentos de docagem. Os resultados mostram o elevado n?vel de qualidade obtido pelos modelos de receptores totalmente flex?veis reduzidos (Reduced Fully-Flexible Receptor - RFFR) ao final dos experimentos em dois conjuntos de an?lises. O primeiro mostra que e-FReDock ? capaz de preservar a qualidade do modelo FFR entre 84,00% e 94,00%, enquanto a sua dimensionalidade reduz em uma m?dia de 49,68%. O segundo relata que os modelos RFFR resultantes s?o capazes de melhorar os resultados de docagem molecular em 97,00% dos ligantes testados quando comparados com a vers?o r?gida do modelo FFR. / The use of conformations obtained from molecular dynamics trajectories in the molecular docking experiments is the most accurate approach to simulate the behavior of receptors and ligands in molecular environments. However, such simulations are computationally expensive and their execution may become an infeasible task due to the large number of structural information, typically considered to represent the explicit flexibility of receptors. In addition, the computational demand increases when Fully-Flexible Receptor (FFR) models are routinely applied for screening of large compounds libraries. This study presents a novel method to optimize docking-based virtual screening of FFR models by reducing the size of FFR models at docking runtime, and scaling docking workflow invocations out onto virtual machines from cloud platforms. For this purpose, we developed e-FReDock, a cloud-based scientific workflow that assists in faster high-throughput docking simulations of flexible receptors and ligands. e-FReDock is based on a free-parameter selective method to perform ensemble docking experiments with multiple ligands from a clustered FFR model. The e-FReDock input data was generated by applying six clustering methods for partitioning conformations with different features in their substrate-binding cavities, aiming at identifying groups of snapshots with favorable interactions for specific ligands at docking runtime. Experimental results show the high quality Reduced Fully-Flexible Receptor (RFFR) models achieved by e-FReDock in two distinct sets of analyses. The first analysis shows that e-FReDock is able to preserve the quality of the FFR model between 84.00% and 94.00%, while its dimensionality reduces on average 49.68%. The second analysis reports that resulting RFFR models are able to reach better docking results than those obtained from the rigid version of the FFR model in 97.00% of the ligands tested.

L'étude structurale de l'interactome cellulaire peut conduire à des découvertes intéressantes sur les bases moléculaires de certaines pathologies. La modélisation par homologie et l'amarrage de protéines ("protein docking") sont deux approches informatiques pour modéliser la structure tri-dimensionnelle (3D) d'une interaction protéine-protéine (PPI). Des études précédentes ont montré que ces deux approches donnent de meilleurs résultats quand des données expérimentales sur les PPIs sont prises en compte. Cependant, les données PPI ne sont souvent pas disponibles sous une forme facilement accessible, et donc ne peuvent pas être re-utilisées par les algorithmes de prédiction. Cette thèse présente une approche systématique fondée sur l'extraction de connaissances pour représenter et manipuler les données PPI disponibles afin de faciliter l'analyse structurale de l'interactome et d'améliorer les algorithmes de prédiction par la prise en compte des données PPI. Les contributions majeures de cette thèse sont de : (1) décrire la conception et la mise en oeuvre d'une base de données intégrée KBDOCK qui regroupe toutes les interactions structurales domaine-domaine (DDI); (2) présenter une nouvelle méthode de classification des DDIs par rapport à leur site de liaison dans l'espace 3D et introduit la notion de site de liaison de famille de domaines protéiques ("domain family binding sites" ou DFBS); (3) proposer une classification structurale (inspirée du système CATH) des DFBSs et présenter une étude étendue sur les régularités d'appariement entre DFBSs en terme de structure secondaire; (4) introduire une approche systématique basée sur le raisonnement à partir de cas pour modéliser les structures 3D des complexes protéiques à partir des DDIs connus. Une interface web (http://kbdock.loria.fr) a été développée pour rendre accessible le système KBDOCK. Le système KBDOCK couvre plus de 2,700 hetero DDIs non-redondantes correspondant à 1,439 DFBSs localisés sur 947 domaines Pfam distincts. KBDOCK a permis de réaliser plusieurs études étendues. Par exemple, KBDOCK a été utilisé pour montrer que: (1) après de 70% de familles de domaines protéiques n'ont qu'un seul DFBS et les autres familles en ont un petit nombre seulement, ce qui suggère que les DDIs re-utilisent souvent les mêmes sites de liaison; (2) plus de 80% de DFBSs interagissent avec une seule famille de domaines protéiques et les autres DFBSs interagissent avec un petit nombre de familles, ce qui indique que la plupart des DFBSs sont principalement monogames dans leur interactions avec les autres domaines protéiques; (3) les DFBSs impliqués dans des interactions présentent des régularités en terme de structure secondaire, ce qui pourrait servir comme un descripteur complémentaire dans la prédiction d'interaction; (4) lorsque les domaines re-utilisent leur DFBS, le docking orienté vient améliorer les prédictions. Ainsi, KBDOCK constitue une ressource unifiée qui permet d'enrichir les connaissances sur l'interactome structural.

El objetivo de la presente tesis es el de aportar conocimiento sobre la bioquímica y la farmacología de los receptores de adenosina, así como entender las relaciones entre estructura química y actividad farmacológica de los ligandos existentes para estos receptores. Con este objetivo se han empleado distintas técnicas y metodologías del diseño de fármacos asistido por ordenador. Los resultados presentados en este trabajo incluyen:· El desarrollo de una estrategia original para la selección de una muestra que cubra adecuadamente la diversidad molecular existente en una base de datos de compuestos químicos· La construcción de un modelo de la región transmembrana del receptor A1 humano de adenosina, en el que se ha localizado y caracterizado un sitio de unión de agonistas compatible con los datos experimentales.· Predicciones teóricas de las energías de unión de ligandos, realizadas a partir de los complejos agonista-receptor predichos sobre el modelo mencionado, obteniendo un grado de acuerdo con los datos experimentales que resulta esperanzador / The goal of the present thesis is to gain knowledge about the biochemistry and pharmacology of adenosine receptors, as well as to understand structure-activity relationships for the existing ligands for this receptors. In order to achieve this goal, we have used several techniques and methodologies from the computer-aided drug design field. Results presented in this work include:· The development of an original strategy of selection of a maximum diversity sample that adequately covers the original molecular diversity contained in a compound database· The building of the transmembrane region of a human A1 adenosine receptor model. In such a model, an agonists binding site has been located and characterized, showing agreement with experimental data.· The resulting ligand-receptor complexes have been studied with computational approaches for the prediction of ligand-binding free energies. A nice correlation with experimental results was observed