Cette thèse est consacrée à la cartographie de l’espace chimique ; son but est d’établir les bases d’un outil donnant une vision d’ensemble d’un jeu de données, comprenant prédiction d’activité, visualisation, et comparaison de grandes librairies. Dans cet ouvrage, nous introduisons des modèles prédictifs QSAR (relations quantitatives structure à activité) avec de nouvelles définitions de domaines d’applicabilité, basés sur la méthode GTM (generative topographic mapping), introduite par C. Bishop et al. Une partie de cette thèse concerne l’étude de grandes librairies de composés chimiques grâce à la méthode GTM incrémentale. Nous introduisons également une nouvelle méthode « Stargate GTM », ou S-GTM, permettant de passer de l’espace des descripteurs chimiques à celui des activités et vice versa, appliquée à la prédiction de profils d’activité ou aux QSAR inverses. / This thesis is dedicated to the cartography of chemical space; our goal is to establish the foundations of a tool offering a complete overview of a chemical dataset, including visualization, activity prediction, and comparison of very large datasets. In this work, we introduce new QSAR models (quantitative structure-activity relationship) based on the GTM method (generative topographic mapping), introduced by C. Bishop et al. A part of this thesis is dedicated to the visualization and analysis of large chemical libraries using the incremental version of GTM. We also introduce a new method coined “Stargate GTM” or S-GTM, which allows us to travel from the space of chemical descriptors to activity space and vice versa; this approach was applied to activity profile prediction and inverse QSAR.

No description available.

No / While mining a data set of 554 chemicals in order to extract information on their toxicity value, we faced the problem of scaling all the data. There are numerous different approaches to this procedure, and in most cases the choice greatly influences the results. The aim of this paper is 2-fold. First, we propose a universal scaling procedure for acute toxicity in fish according to the Directive 92/32/EEC. Second, we look at how expert preprocessing of the data effects the performance of qualitative structure-activity relationship (QSAR) approach to toxicity prediction.

Studies into the quantitative structure act! Vlty relationships of rate s of I-methyl-4-phenyl-l,2,3,6-tetrahydropyridine oxidation catalyzed by monoamine oxidases A and B were performed to elucidate active site substrate conformation and oxidation mechanisms. Plotting experimental kinetic activity against molecular properties obtained by experiment and by computational chemistry methods demonstrated correlations with lipophilic, steric, and electronic factors. Compounds studied were 4-aryloxy analogs, 4- aromatic heterocycle analogs, and 4-phenyl analogs. The conformer with phenyl ring to tetrahydropyridine dihedral angles similar to a low energy conformer of I-methyl-4-(2'-methyl-phenyl)-1,2,3,6- tetrahydropyridine is the most active conformer. Results indicate that rate limiting single electron transfer mechanisms are more viable than hydrogen atom abstraction mechanisms. Results indicate that binding or dissociation is the rate limiting step for aryloxy-analog oxidation catalyzed by monoamine oxidase B whereas the catalytic event itself is the rate limiting step for the other analogs. Several equations were developed to describe quantitative structure activity relationships of oxidation rates. / Master of Science

No / L-type voltage gated calcium channels play essential role in contraction of various skeletal and vascular smooth muscles, thereby plays important role in regulating blood pressure. Dihydropyridine receptors have been targeted for development of newer antihypertensive agents, one of the structurally analogs nucleus dihydropyrimidines have been reported earlier by us as a potential agent toward development of calcium channel modulator. A pre-synthetic QSAR was run and on the basis of structure activity relationship a series of twenty three molecules was synthesized and studied by myosin light chain kinase assay (MLCK), Angiotensin Converting Enzyme (ACE) colorimetric assay, non-invasive blood pressure (NIBP) and invasive blood pressure (IBP) methods. Molecules with significant efficacy were studied for their single crystal X-ray diffraction, molecular docking, molecular dynamics and post-synthetic QSAR. The NIBP and IBP methods screened molecules with better percentage inhibition versus time compared to standard drug Nifedipine. The lead compound ethyl 2-methyl-4-(3-nitrophenyl)-4H-pyrimido [2,1-b] [1,3] benzothiazole-3-carboxylate (26) presented a triclinic structure with polymeric chain packing in lattice. 26 exhibited IC50 on MLCK assay of 2.1+/-1.7 muM with selectivity of L-type calcium channels and comparative to Nifedipine. It offered satisfactory physicochemical properties with partition coefficient of (ClogP) 4.64. Its pharmacokinetic profile is also good with Cmax at 0.40 mug/ml by oral route with Tmax reaching in 0.5 h which means in 30 min. 26 also exhibits superior t1/2 of 5.4 h and oral bioavailability of (F) 56.75% with an AUC0-infinity of 0.84 mug h/ml. Molecular docking studies indicates toward the interaction of lead compound via hydrogen bonds with Lys144, Glu181 and Asp183, it forms the Van der Walls interactions with Ser18, Asp20, Asn187, Pro185, Glu180, Glu181 and Arg10 with Glide score and Glide energy to be -3.602 and -47.098, respectively. Post-synthetic QSAR of newly synthesized molecules indicates toward improvement with respect to steric descriptor which contributed negatively in former series.

When applied to drug discovery, modern computational systems can provide insight into the highly complex systems underlying drug activity and predict compounds or targets of interest. Many tools have been developed for computer aided drug discovery (CADD), focusing on small molecule ligands, protein targets, or both. The aim of this thesis is the improvement of CADD tools for describing small molecule properties and application of CADD to several stages of drug discovery regarding two targets for the treatment of obesity and related diseases: the neuropeptide Y4 receptor (Y4R) and the melanocortin-4 receptor (MC4R). In the first chapter, the major categories of CADD are outlined, including descriptions for many of the popular tools and examples where these tools have directly contributed to the discovery of new drugs. Following the introduction, several improvements for encoding stereochemistry and signed property distribution are introduced and tested in scenarios meant to simulate applications in virtual high-throughput screening. Y4R and MC4R are both class A G-protein coupled receptors (GPCRs) with endogenous peptide ligands that play critical roles in the signaling of satiety and energy metabolism. So far, no structures from either receptor family have been experimentally elucidated. CADD was combined with high-throughput screening (HTS) to discover the first small molecule positive allosteric modulators (PAMs) of Y4R. Secondly, CADD techniques were used to model the interaction of Y4R and pancreatic polypeptide based on experimental results that elucidate specific binding contacts. Similar SB-CADD approaches were used to model the interaction of MC4R with its high affinity peptide agonist α-MSH. Due to its role in monogenic forms of obesity, these models were used to predict which residues directly participate in binding and correlate mutated residues with their potential role in the binding site.

A serotonina e a histamina são duas das mais importantes aminas biogênicas do organismo. Regulam série de funções fisiológicas, como fluxo sanguíneo, temperatura corpórea, sono, fome, liberação de hormônios, comportamento afetivo e humor, entre outras. Assim, há grande interesse no planejamento e desenvolvimento de fármacos que interferem na transmissão serotoninérgica e histaminérgica, para futura aplicação como antidepressivos, antipsicóticos, ansiolíticos e anorexígenos, além de perifericamente, apresentarem possíveis ações antiinflamatórias. O objetivo deste trabalho é apresentar a síntese de compostos contendo os núcleos pirrolquinolínico, benzoindólico e benzodiidrofurânico com potencial atividade ligante nos receptores 5-HT2C e H4, assim como avaliar a seletividade desses compostos em comparação aos receptores 5-HT2A/B e H3. Sintetizou-se série de compostos utilizando reações de alilação, adição à carbonila, termociclização, rearranjo de Claisen, iodociclização e substituição nucleofílica para a obtenção dos compostos finais. Estudos de otimização de síntese por metodologia de superfície de resposta também são apresentados, assim como estudos de relações quantitativas entre estrutura química e atividade biológica de compostos ligantes dos receptores 5-HT2C e H4. / Serotonin and histamine are two major biogenic amines in the body. They regulate several physiological functions such as blood flow, body temperature, sleep, hunger, hormone release, emotional behavior and mood, among others. Thus, there is great interest in the design and development of drugs that interfere with serotoninergic and histaminergic transmission, for future use as antidepressants, antipsychotics, anxiolytics and anorectic, and peripherally, possible anti-inflammatory actions. The aim of this work is to present the synthesis of compounds containing the pyrroloquinoline, benzoindole and benzodihydrofurane nucleus with potential binding activity to 5-HT2C and H4 receptors, as well as to evaluate the selectivity of these compounds in comparison to 5-HT2A/B and H3. Series of compounds were synthesized using allylation, carbonyl addition, thermal cyclization, Claisen rearrangement, iodocyclization and nucleophilic substitution reactions. Optimization studies for the synthesis using response surface methodology are also presented, as well as quantitative structure-activity relationships studies of ligands of 5-HT2C and H4 receptors.

A doença de Chagas afeta cerca de 6 a 7 millhões de pessoas no mundo, principalmente América Latina. A busca de alternativas terapêuticas para esta enfermidade tem grande relevância para a sociedade, já que as opções atuais são limitadas, sendo disponível apenas o benznidazol (BZD) e nifurtimox. Os derivados nitroheterocíclicos são considerados compostos bioativos com número crescente de estudos na comunidade científica contra seu agente etiológico, o Trypanosoma cruzi. Neste sentido, o presente trabalho tem por objetivo a identificação de derivados do 5-nitrofurano com atividade frente a diferentes cepas do T. cruzi, assim como estudar possíveis modo de ação desta classe de compostos. Esta investigação envolve estudos computacionais com o propósito de construir modelos quantitativos de relações estrutura-atividade (QSAR multivariado) que possam auxiliar na previsão de novas estruturas com perfil farmacológico otimizado. No presente trabalho foram realizadas as etapas de planejamento, síntese e identificação de 36 compostos com resultados satisfatórios quanto à identificação estrutural, pureza e rendimento, que foi da ordem de 70%. A determinação da atividade anti-T. cruzi in vitro dos compostos obtidos foi realizada frente às cepas Silvio X10 cl1, Y, Bug 2149 cl10 e Colombiana na forma epimastigota do parasito. A maioria dos compostos analisados apresentou maior capacidade de inibição de crescimento do parasito, comparado ao BZD: Silvio X10 cl1 - IC50 = 29,16 ±2,90 µM, Y - IC50 = 40,40 ±3,37µM, Bug 2149 cl10 - IC50 = 30,63 ±3,21 µM, Colombiana - IC50 = 47,91 ±4,96 µM. O composto mais ativo (BSF-35) apresentou os seguintes valores: Silvio X10 cl1 - IC50 = 3,17 ±0,32 µM, Y - IC50 = 1,17 ±0,12 µM, Bug 2149 cl10 - IC50 = 1,81 ±0,18 µM e Colombiana - IC50 = 3,06 ±0,23 µM. Foram realizados cálculos de propriedades moleculares das estruturas tridimensionais dos compostos, seguido pela análise exploratória de dados por análise de agrupamentos hierárquicos (HCA) e análise de componentes principais (PCA), possibilitando o reconhecimento de padrões do conjunto. Considerando esta análise prévia, foram obtidos modelos QSAR com abordagem multivariada, aplicando algorítmo OPS e método de regressão por quadrados mínimos parciais, PLS. Os melhores modelos gerados foram obtidos considerando os compostos benzenos substituídos para as quatro cepas estudadas. Os descritores que mais influenciaram na análise foram o ClogP (coeficiente de partição) e cargas CHELPG. Considerando as informações obtidas, foram planejados e sintetizados quatro novos compostos com objetivo de obter compostos mais ativos e validar os modelos QSAR. Estes compostos apresentaram alta atividade frente a forma epimastigota das quatro cepas estudadas. Os compostos mais ativos foram avaliados quanto a citotoxicidade frente células LLC-MK2 e apresentaram seletividade até 25 vezes superior ao BZD. Estudos in vitro frente a forma amastigota da cepa Y em células U2OS foram realizados com metodologia fenotípica de análise de alto conteúdo (HCA\') e os compostos apresentaram atividade até 64 vezes superior ao BZD e com seletividade de até 50 vezes superior a este fármaco. Quanto à determinação da atividade dos compostos frente às enzimas tripanotiona redutase (TcTR) e glutationa redutase (GR), os compostos analisados não apresentaram atividade relevante, indicando não ser este o mecanismo desta classe de compostos. Com finalidade de explorar outro possível mecanismo de ação dos compostos 5-nitrofurânicos, foi realizada a análise de potencial de redução da membrana mitocondrial, porém a morte parasitária não foi atribuída à despolarização da membrana em estudos simultâneos com iodeto de propídio. / Chagas disease affects approximately 6-7 millions people worldwide, especially Latin America. The search for therapeutic alternatives for this disease is of great relevance to society, as current options are limited and there are only two available drugs: benznidazole (BZD) and nifurtimox. The nitroheterocyclic derivatives are considered bioactive compounds with increasing number of studies in the scientific community against its etiologic agent, Trypanosoma cruzi. In this sense, this work aims to identify derivatives of 5-nitrofuran with activity against different strains of T. cruzi, and to study possible mode of action of this compounds. This research involves computational studies to obtain models of quantitative structure-activity relationships (QSAR multivariate) that can help predict new structures with optimized pharmacological profile. In this work were carried out the design, synthesis and identification of 36 compounds with satisfactory results regarding the structural identification, purity and yield (approximately 70%). The determination of anti-T. cruzi activity in vitro of the compounds obtained was carried out with Silvio X10 cl1, Y, Bug 2149 CL10 and Colombiana strains of epimastigote form of the parasite. Most of the compounds examined showed greater capacity of growth inhibition of the parasite compared to the BZD (Silvio X10 CL1 - IC 50 = 29.16 ± 2.90 µM, Y - IC50 = 40.40 ± 3,37µM, 2149 CL10 Bug - IC 50 = 30.63 ± 3.21 µM, Colombiana - IC 50 = 47.91 ± 4.96 µM). The most active compound (BSF-35) showed the following values: Silvio X10 cl1 - IC 50 = 3.17 ± 0.32 uM, Y - IC 50 = 1.17 ± 0.12 µM, Bug 2149 CL10 - IC50 = 1, 81 ± 0.18 µM and Colombiana - IC 50 = 3.06 ± 0.23 µM. Calculations were performed for the molecular properties of three-dimensional structures of the compounds, followed by exploratory data analysis by hierarchical cluster analysis (HCA) and principal component analysis (PCA), allowing the recognition of the set. Considering this preliminary analysis were obtained QSAR models with multivariate approach, using OPS algorithm and regression method of partial least squares, PLS. The best generated models were obtained considering the benzyl substituted compounds for the four strains. The descriptors that most influenced the analysis were ClogP (partition coefficient) and CHELPG charges. Considering the information obtained, four new compounds were designed and synthesized to obtain more active compounds and validate QSAR models. These compounds showed high activity against epimastigote form of the four strains studied. The most active compounds were evaluated for cytotoxicity against LLC-MK2 cells and the compounds selectivity values were up to 25 times higher than BZD. In vitro studies against amastigote form of the Y strain in U2OS cells were performed with phenotypic method of high content analysis (HCA\') and the compounds showed activity to 64 times higher than BZD and selectivity of up to 50 times. The activity of the compounds against trypanothione reductase enzymes (TcTR) and glutathione reductase (GR) showed no significant activity, indicating that this is not the mechanism of this class of compounds. In order to exploit another possible mechanism of action of 5-nitrofuran derivatives, analysis reduction of mitochondrial membrane potential was held, however the cell death was not attributed to membrane depolarization in simultaneous studies with propidium iodide.

A doença de Chagas afeta cerca de 6 a 7 millhões de pessoas no mundo, principalmente América Latina. A busca de alternativas terapêuticas para esta enfermidade tem grande relevância para a sociedade, já que as opções atuais são limitadas, sendo disponível apenas o benznidazol (BZD) e nifurtimox. Os derivados nitroheterocíclicos são considerados compostos bioativos com número crescente de estudos na comunidade científica contra seu agente etiológico, o Trypanosoma cruzi. Neste sentido, o presente trabalho tem por objetivo a identificação de derivados do 5-nitrofurano com atividade frente a diferentes cepas do T. cruzi, assim como estudar possíveis modo de ação desta classe de compostos. Esta investigação envolve estudos computacionais com o propósito de construir modelos quantitativos de relações estrutura-atividade (QSAR multivariado) que possam auxiliar na previsão de novas estruturas com perfil farmacológico otimizado. No presente trabalho foram realizadas as etapas de planejamento, síntese e identificação de 36 compostos com resultados satisfatórios quanto à identificação estrutural, pureza e rendimento, que foi da ordem de 70%. A determinação da atividade anti-T. cruzi in vitro dos compostos obtidos foi realizada frente às cepas Silvio X10 cl1, Y, Bug 2149 cl10 e Colombiana na forma epimastigota do parasito. A maioria dos compostos analisados apresentou maior capacidade de inibição de crescimento do parasito, comparado ao BZD: Silvio X10 cl1 - IC50 = 29,16 ±2,90 µM, Y - IC50 = 40,40 ±3,37µM, Bug 2149 cl10 - IC50 = 30,63 ±3,21 µM, Colombiana - IC50 = 47,91 ±4,96 µM. O composto mais ativo (BSF-35) apresentou os seguintes valores: Silvio X10 cl1 - IC50 = 3,17 ±0,32 µM, Y - IC50 = 1,17 ±0,12 µM, Bug 2149 cl10 - IC50 = 1,81 ±0,18 µM e Colombiana - IC50 = 3,06 ±0,23 µM. Foram realizados cálculos de propriedades moleculares das estruturas tridimensionais dos compostos, seguido pela análise exploratória de dados por análise de agrupamentos hierárquicos (HCA) e análise de componentes principais (PCA), possibilitando o reconhecimento de padrões do conjunto. Considerando esta análise prévia, foram obtidos modelos QSAR com abordagem multivariada, aplicando algorítmo OPS e método de regressão por quadrados mínimos parciais, PLS. Os melhores modelos gerados foram obtidos considerando os compostos benzenos substituídos para as quatro cepas estudadas. Os descritores que mais influenciaram na análise foram o ClogP (coeficiente de partição) e cargas CHELPG. Considerando as informações obtidas, foram planejados e sintetizados quatro novos compostos com objetivo de obter compostos mais ativos e validar os modelos QSAR. Estes compostos apresentaram alta atividade frente a forma epimastigota das quatro cepas estudadas. Os compostos mais ativos foram avaliados quanto a citotoxicidade frente células LLC-MK2 e apresentaram seletividade até 25 vezes superior ao BZD. Estudos in vitro frente a forma amastigota da cepa Y em células U2OS foram realizados com metodologia fenotípica de análise de alto conteúdo (HCA\') e os compostos apresentaram atividade até 64 vezes superior ao BZD e com seletividade de até 50 vezes superior a este fármaco. Quanto à determinação da atividade dos compostos frente às enzimas tripanotiona redutase (TcTR) e glutationa redutase (GR), os compostos analisados não apresentaram atividade relevante, indicando não ser este o mecanismo desta classe de compostos. Com finalidade de explorar outro possível mecanismo de ação dos compostos 5-nitrofurânicos, foi realizada a análise de potencial de redução da membrana mitocondrial, porém a morte parasitária não foi atribuída à despolarização da membrana em estudos simultâneos com iodeto de propídio. / Chagas disease affects approximately 6-7 millions people worldwide, especially Latin America. The search for therapeutic alternatives for this disease is of great relevance to society, as current options are limited and there are only two available drugs: benznidazole (BZD) and nifurtimox. The nitroheterocyclic derivatives are considered bioactive compounds with increasing number of studies in the scientific community against its etiologic agent, Trypanosoma cruzi. In this sense, this work aims to identify derivatives of 5-nitrofuran with activity against different strains of T. cruzi, and to study possible mode of action of this compounds. This research involves computational studies to obtain models of quantitative structure-activity relationships (QSAR multivariate) that can help predict new structures with optimized pharmacological profile. In this work were carried out the design, synthesis and identification of 36 compounds with satisfactory results regarding the structural identification, purity and yield (approximately 70%). The determination of anti-T. cruzi activity in vitro of the compounds obtained was carried out with Silvio X10 cl1, Y, Bug 2149 CL10 and Colombiana strains of epimastigote form of the parasite. Most of the compounds examined showed greater capacity of growth inhibition of the parasite compared to the BZD (Silvio X10 CL1 - IC 50 = 29.16 ± 2.90 µM, Y - IC50 = 40.40 ± 3,37µM, 2149 CL10 Bug - IC 50 = 30.63 ± 3.21 µM, Colombiana - IC 50 = 47.91 ± 4.96 µM). The most active compound (BSF-35) showed the following values: Silvio X10 cl1 - IC 50 = 3.17 ± 0.32 uM, Y - IC 50 = 1.17 ± 0.12 µM, Bug 2149 CL10 - IC50 = 1, 81 ± 0.18 µM and Colombiana - IC 50 = 3.06 ± 0.23 µM. Calculations were performed for the molecular properties of three-dimensional structures of the compounds, followed by exploratory data analysis by hierarchical cluster analysis (HCA) and principal component analysis (PCA), allowing the recognition of the set. Considering this preliminary analysis were obtained QSAR models with multivariate approach, using OPS algorithm and regression method of partial least squares, PLS. The best generated models were obtained considering the benzyl substituted compounds for the four strains. The descriptors that most influenced the analysis were ClogP (partition coefficient) and CHELPG charges. Considering the information obtained, four new compounds were designed and synthesized to obtain more active compounds and validate QSAR models. These compounds showed high activity against epimastigote form of the four strains studied. The most active compounds were evaluated for cytotoxicity against LLC-MK2 cells and the compounds selectivity values were up to 25 times higher than BZD. In vitro studies against amastigote form of the Y strain in U2OS cells were performed with phenotypic method of high content analysis (HCA\') and the compounds showed activity to 64 times higher than BZD and selectivity of up to 50 times. The activity of the compounds against trypanothione reductase enzymes (TcTR) and glutathione reductase (GR) showed no significant activity, indicating that this is not the mechanism of this class of compounds. In order to exploit another possible mechanism of action of 5-nitrofuran derivatives, analysis reduction of mitochondrial membrane potential was held, however the cell death was not attributed to membrane depolarization in simultaneous studies with propidium iodide.

A dor neuropática atinge cerca de 6 a 10% da população global e estima-se o seu aumento nos próximos anos. Essa síndrome não tem cura e afeta consideravelmente a qualidade de vida das pessoas por ela acometidas. Os medicamentos utilizados atualmente para o seu tratamento, como antidepressivos, anticonvulsivantes, opióides, dentre outros, não proporcionam um resultado satisfatório pelo fato de não reduzirem consideravelmente os sintomas e/ou por terem muitos efeitos colaterais. Pesquisas recentes mostram que o receptor sigma-1 pode ser utilizado no tratamento da dor neuropática. Verificou-se na literatura uma nova série de pirimidinas que são capazes de se ligar ao receptor sigma-1, atuando como seus antagonistas, sendo potenciais alvos para a produção de fármacos que podem ser utilizados no tratamento da dor neuropática. Então, estudos de Relações Quantitativas Estrutura-Atividade (QSAR) foram realizados utilizando os métodos de Mínimos Quadrados Parciais (PLS) e Redes Neurais Artificiais (ANN) para prever a atividade biológica dessa série de pirimidinas. Os resultados obtidos se mostraram satisfatórios tanto para o método de PLS (r2 = 0,877, q2 = 0,800 e r2teste = 0,738), quanto para o método de ANN (r2trein = 0,734, r2val = 0,753 e r2teste = 0,676), mostrando que o conjunto de compostos antagonistas do receptor Sigma-1 pode ser descrito tanto de forma linear quanto de forma não-linear. / Neuropathic pain affects about 6 to 10% of the global population and it is estimated to increase in the coming years. This syndrome has no cure and considerably affects the life quality of people affected by it. Medications currently used for its treatment, such as antidepressants, anticonvulsants, opioids, among others, do not provide a satisfactory result because they do not significantly reduce the symptoms and/or have many side effects. Recent research shows that the sigma-1 receptor can be used in the treatment of the neuropathic pain. A new series of pyrimidines have been found in the literature, which are capable of binding to the sigma-1 receptor, acting as its antagonists, and have been synthesized as potential targets that can be used in the treatment of the neuropathic pain. Therefore, Quantitative Structure-Activity Relationships (QSAR) were performed using Partial Least Squares (PLS) and Artificial Neural Networks (ANN) methods to predict the biological activity of this series of pyrimidines. Through the mathematical models obtained by PLS (r2 = 0.877, q2 = 0.800 and r2test = 0.738) and ANN (r2trein = 0.734, r2val = 0.753 and r2test = 0.676) methods, it was showed that they were able to predict the biological activity of the studied pyrimidines.