A new approach to analysis of protein-ligand interactions, termed proteochemometrics, has been developed. Contrary to traditional quantitative structure-activity relationship (QSAR) methods that aim to correlate a description of ligands to their interactions with one particular target protein, proteochemometrics considers many targets simultaneously. Proteochemometrics thus analyzes the experimentally determined protein-ligand interaction activity data by correlating the data to a complex description of all interaction partners and; in a more general case even to interaction environment and assaying conditions, as well. In this way, a proteochemometric model analyzes an “interaction space,” from which only one cross-section would be contemplated by any one QSAR model. Proteochemometric models reveal the physicochemical and structural properties that are essential for protein-ligand complementarity and determine specificity of molecular interactions. From a drug design perspective, models may find use in the design of drugs with improved selectivity and in the design of drugs for multiple targets, such as mutated proteins (e.g., drug resistant mutations of pathogens). In this thesis, a general concept for creating of proteochemometric models and approaches for validation and interpretation of models are presented. Different types of physicochemical and structural description of ligands and macromolecules are evaluated; mathematical algorithms for proteochemometric modeling, in particular for analysis of large-scale data sets, are developed. Artificial chimeric proteins constructed according to principles of statistical design are used to derive high-resolution models for small classes of proteins. The studies of this thesis use data sets comprising ligand interactions with several families of G protein-coupled receptors. The presented approach is, however, general and can be applied to study molecular recognition mechanisms of any class of drug targets.

This thesis deals with the highly potent olfactory mucosa toxicant 2,6-dichlorophenyl methylsulphone (2,6-diClPh-MeSO2) and its non-toxic 2,5-chlorinated isomer (2,5-diClPh-MeSO2). In mice, both substances bind firmly in the olfactory mucosa and the olfactory bulb, which are important components of the sensory system. The 2,6-isomer induces olfactory mucosal necrosis with permanent loss of olfactory neuroepithelium and olfactory nerves. A major objective was to clarify the cause of this isomer-specific toxicity, and to identify which physicochemical characteristics determine the olfactory toxicity. The neurobehavioural toxicity of these substances was also examined. The results revealed a rapid CYP-catalysed covalent binding of 2,6-diClPh-MeSO2 in the rat olfactory mucosa, whereas the 2,5-dichlorinated isomer was not covalently bound. Acute and chronic olfactory mucosal pathology were investigated and compared in rats and mice. Twenty-four hours after dosing to rats, 2,6-diClPh-MeSO2 induced Bowman’s glands necrosis and sloughing of the olfactory epithelium similar to that previously reported in mice. At 3 weeks, however, there were dramatic differences in histological lesions. In mice, large parts of olfactory epithelium were replaced by respiratory-like epithelium. Large, bilateral, fibrous, cartilage and bone containing polyps occluding the lumen were confirmed. In rats, only minor patches of olfactory epithelium were replaced by a metaplastic atypical respiratory-like epithelium. 2,5-diClPh-MeSO2 was non-toxic in rats as well as in mice. In mice, 2,6-diClPh-MeSO2 induced a dose-dependent and long-lasting ( ≥12 weeks) hyperactivity as well as long-lasting maze learning deficits. At 2 weeks hyperactivity and maze learning deficits were observed also in rats. Unexpectedly, 2,5-diClPh-MeSO2 induced hyperactivity that lasted for two weeks. No effect on maze learning was observed with this isomer. No major differences between male and female rats or mice were found. In conclusion, the results show that a CYP-catalysed formation and covalent binding of a reactive 2,6-diClPh-MeSO2-metabolite in the Bowman’s glands precede the high olfactory mucosal toxicity in rodents. As determined by QSAR-modelling, a 2,6-dichlorinated benzene derivative with a large, polar, and strong electron withdrawing substituent in the primary position has the potential of being an olfactory mucosal toxicant. The observed 2,6-diClPh-MeSO2-induced increase in motor activity, and maze learning deficits, were not correlated to the olfactory mucosal lesions. I propose that 2,6-diClPh-MeSO2 causes a direct effect in the brain leading to neurobehaviuoral deficits.

Type III secretion is a virulence system utilized by several clinically important Gram-negative pathogens. Computational methods have been used to develop two classes of type III secretion inhibitors, the salicylidene acylhydrazides and the acetylated salicylanilides. For these classes of compounds, quantitative structure-activity relationship models have been constructed with data from focused libraries obtained by statistical molecular design. The models have been validated and shown to provide useful predictions of untested compounds belonging to these classes. Scaffold hopping of the salicylidene acylhydrazides have resulted in a number of synthetic targets that might mimic the scaffold of the compounds. The synthesis of two libraries of analogs to two of these scaffolds and the biological evaluation of them is presented.

Food protein-derived peptides have increasingly become important sources of ingredients for the formulation of therapeutic products. The main aim of this work was to study the in vitro and in vivo bioactive properties of structurally diverse group of peptides produced through enzymatic hydrolysis of flaxseed proteins (FP). Hydrolysis of FP with seven proteases followed by fractionation into low-molecular-weight (LMW) cationic fractions yielded multifunctional peptides that inhibited angiotensin converting enzyme (ACE) and renin activities, which are molecular targets for antihypertensive agents. The LMW peptides also exhibited antioxidant properties by scavenging free radicals and inhibiting amine oxidase activity. The peptide fractions showed inhibition of calmodulin-dependent phosphodiesterase, an enzyme that has been implicated in the pathogenesis of several chronic diseases. Moreover, FP hydrolysis with thermolysin and pronase followed by mixing with activated carbon yielded branched-chain amino acids (BCAA)-enriched multifunctional peptide mixture (Fischer ratio of 23.65) with antioxidant properties and in vitro ACE inhibition; Fischer ratio of 20.0 is considered minimum for therapeutic purposes. The BCAA-enriched peptide product can be used in clinical nutrition to treat muscle wasting symptoms associated with hepatic diseases. Furthermore, an arginine-rich peptide mixture (31% arginine versus 11% in the original flaxseed protein) was produced by hydrolysis of FP with trypsin and pronase followed by separation using electrodialysis-ultrafiltration. Arginine plays important physiological roles especially as precursor to vasodilator, nitric oxide. The arginine-rich peptide mixture exhibited in vitro ACE and renin inhibition and led to decreased systolic blood pressure (–17.9 and –11.7 mmHg, respectively at 2 and 4 h) after oral administration to spontaneously hypertensive rats. For the first time in the literature, we showed that arginine peptides have superior physiological effects when compared to the amino acid form of arginine. Lastly, quantitative structure-activity relationship studies using partial least squares (PLS) regression yielded two predictive models for renin-inhibiting dipeptides with z-scales amino acid descriptors. The PLS models indicated that hydrophobic and bulky side chain-containing amino acids contribute to renin inhibition if present at the amino- and carboxyl-terminal of dipeptides, respectively. Based on this study, Ile-Trp was discovered as potent renin-inhibiting dipeptide, and may serve as a useful template for the development of potent antihypertensive peptidomimetics.

A systematic methodology for quantitative structure-activity relationship (QSAR) development in environmental toxicology is provided. The methodology is summarized in a strategy with six sequential steps. The strategy rests on two cornerstones, namely (1) the use of statistical design to select a series of representative compounds (the so-called training set) on which to base a QSAR, and (2) the multivariate modelling of the relationship between physicochemical and biological properties of the training set compounds. The first step of the strategy is the division of chemicals into classes of structurally similar compounds. Briefly, steps 2 to 6 are: (2) physico-chemical and structural characterization of the compounds in a class, (3) selection of a training set of representative compounds, (4) biological testing of the selected training set, (5) QSAR model development, and (6) experimental validation of the QSAR and predictions for non-tested compounds. The thesis summarizes the results obtained from the application of the strategy to the class of halogenated aliphatic compounds. Biological measurements were made in four biological test systems, reflecting acute toxicity, mutagenicity, relative cytotoxicity and genotoxicity. QSARs were developed relating each biological endpoint to the structural descriptors of the compounds. Multivariate PLS modelling was used in the data analysis. The developed QSARs were used for predicting the biological activity pattern of the non-tested compounds in the class. These predictions may be used as a starting point for a priority ranking for further biological testing of these compounds. The strategy has not been developed solely for establishing QSARs for the halogenated aliphatics class. On the contrary, this work is intended to demonstrate a generally applicable QSAR methodology. / <p>Diss. (sammanfattning) Umeå : Umeå universitet, 1991</p> / digitalisering@umu

Food protein-derived peptides have increasingly become important sources of ingredients for the formulation of therapeutic products. The main aim of this work was to study the in vitro and in vivo bioactive properties of structurally diverse group of peptides produced through enzymatic hydrolysis of flaxseed proteins (FP). Hydrolysis of FP with seven proteases followed by fractionation into low-molecular-weight (LMW) cationic fractions yielded multifunctional peptides that inhibited angiotensin converting enzyme (ACE) and renin activities, which are molecular targets for antihypertensive agents. The LMW peptides also exhibited antioxidant properties by scavenging free radicals and inhibiting amine oxidase activity. The peptide fractions showed inhibition of calmodulin-dependent phosphodiesterase, an enzyme that has been implicated in the pathogenesis of several chronic diseases. Moreover, FP hydrolysis with thermolysin and pronase followed by mixing with activated carbon yielded branched-chain amino acids (BCAA)-enriched multifunctional peptide mixture (Fischer ratio of 23.65) with antioxidant properties and in vitro ACE inhibition; Fischer ratio of 20.0 is considered minimum for therapeutic purposes. The BCAA-enriched peptide product can be used in clinical nutrition to treat muscle wasting symptoms associated with hepatic diseases. Furthermore, an arginine-rich peptide mixture (31% arginine versus 11% in the original flaxseed protein) was produced by hydrolysis of FP with trypsin and pronase followed by separation using electrodialysis-ultrafiltration. Arginine plays important physiological roles especially as precursor to vasodilator, nitric oxide. The arginine-rich peptide mixture exhibited in vitro ACE and renin inhibition and led to decreased systolic blood pressure (–17.9 and –11.7 mmHg, respectively at 2 and 4 h) after oral administration to spontaneously hypertensive rats. For the first time in the literature, we showed that arginine peptides have superior physiological effects when compared to the amino acid form of arginine. Lastly, quantitative structure-activity relationship studies using partial least squares (PLS) regression yielded two predictive models for renin-inhibiting dipeptides with z-scales amino acid descriptors. The PLS models indicated that hydrophobic and bulky side chain-containing amino acids contribute to renin inhibition if present at the amino- and carboxyl-terminal of dipeptides, respectively. Based on this study, Ile-Trp was discovered as potent renin-inhibiting dipeptide, and may serve as a useful template for the development of potent antihypertensive peptidomimetics.

L'objet de cette thèse sont les habitations du bilâd al-Shâm à l'époque omeyyade bâties ex-novo; parmi ce groupe ont été sélectionnées les habitations conservées complètes ou dont le plan peut être complètement reconstruit. Les habitations peuvent être distinguées entre habitations des contextes urbains et extra-urbains. Les sites urbains examinés sont : Jerash, 'Anjar, al-FihI, 'Amman et Qaysariyya. Cependant, les seules données qui peuvent être considérées sont celles relatives aux sites de 'Anjar et 'Amman. Les habitions extra palatium de ces deux contextes révèlent analogie en ce qui concerne le statut des habitants, quoique les habitations de 'Anjar montrent une richesse majeure par rapport à celles de 'Amman ; au contraire, les résidences palatine des deux sites ne révèlent pas des analogies : les «palais» et, par conséquent, les habitations ou les unités d'habitations, peuvent être considérées des unica. Les Syrian bayt des contextes urbains et extra-urbains constituent le modèle d'habitation caractéristique de l'élite du bilâd al-Shâm omeyyade ; on les trouve toujours dans des habitations pourvus d'un vestibule et court centrale. Les courts se trouvent toujours dans les habitations du bilâd al-Shâm dans la période omeyyade, mais elles ont apparemment étés sacrifiés dans les cas de lotissement des habitations extra palatium en unités d'habitation (al-FihI, 'Amman). Les dimensions des Syrian bayt des qusür augmentent au cours du temps et sont distinctes en trois phases chronologiques, qui correspondent à trois périodes: le califat de al-Walïd 1er, les premiers dix ans du califat de llishâm ibn 'Abd al-Malik, l'année de règne de al-Walïd 2nd. Les Persian bayt sont absents dans les qusür omeyyades et se trouvent seulement dans la dâr al-imâra de 'Amman. La présence assez importante du Syrian bayt indique que le choix des planimétries d'habitations du type élitaire du bilâd al-Shâm omeyyade était lié à une tradition constructive du territoire syro-palestinien. / This thesis focus on the ex-novo dwellings of bilâd al-Shâm; among this group were considered just the well preserved dwellings or those whose plan can be completely reconstructed. Dwellings can be divided into dwellings of the urban and extra-urban contexts. The examined urbans sites are: Jerash, 'Anjar, al-FihI, 'Amman and Qaysairiyya. Anyway, as for the general considerations the only useful data are those of 'Anjar and 'Amman. Concerning the inhabitants status, the extra­palatium dwellings of these sites reveal some similarities, albeit 'Anjar dwellings show more richness than those of 'Amman; on the contrary, palatine dwellings of both sites doesn't show similarities: "palaces" and consequently dwellings of both sites can be considered as unica. "Syrian bayts" of both urbans and extra-urbans contexts can be considered as characteristics of the Umayyad élite of bilâd al-Shâm; they can always be found in dwellings with a vestibule and a central court. The court in tum can always be found in Umayyad dwellings of bilâd al-Shâm, but they were subdivided in small "residence units" in extra-palatium dwellings parceling cases (al-FihI, 'Amman). Qusur's "Syrian bayts" dimensions increases over time and can be subdivided in three chronological phases, corresponding to three periods: the caliphate of al-Walïd 1st, the first ten years of Hisham ibn 'Abd al-Malik caliphate, the one year caliphate of al-Walïd 2nd. "Persian bayts" are lacking in Umayyad qusur and can be found only in the dâr al-lmâra of 'Amman. The significant presence of "Syrian bayts" show that the elitist Umayyad dwellings of bilâd al-Shâm derives from the construction tradition of the Syrian-Palestinian territory.

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Físicas e Matemáticas. Programa de Pós-Graduação em Química. / Made available in DSpace on 2013-07-15T23:42:18Z (GMT). No. of bitstreams: 0 / Cálculos de regressão linear foram efetuados com o objetivo de estabelecer relações quantitativas entre a atividade antiespasmódica de derivados da xantoxilina e suas propriedades físico-químicas, calculadas através do método semi-empírico AM1. Propriedades globais como calor de formação, energia de hidratação, momento de dipolo, logaritmo do coeficiente de partição octanol-água, área superficial, volume molecular, energias dos orbitais HOMO e LUMO, polarizabilidade, refratividade e a distribuição de cargas parecem não exercer influência sobre a atividade. A análise das superfícies de potencial eletrostático molecular também não trouxe informações conclusivas sobre a variabilidade dos valores de log(1/C). Por outro lado, a análise da distribuição dos orbitais HOMO e LUMO em partes diferentes da estrutura dos compostos estudados, juntamente com os valores de log(1/C), revelou um padrão que explica satisfatoriamente a atividade antiespasmódica desses derivados. Cálculos de regressão linear múltipla utilizando índices de reatividade de átomos específicos e as somas desses índices em partes diferentes dos compostos estudados levaram a equações que quantificam satisfatoriamente a relação dessas propriedades com a atividade. As previsões feitas com as equações obtidas nesse estudo foram comparadas às previsões de equações obtidas em estudos anteriores. Essa comparação sugere quais compostos deveriam ser alvos prioritários para síntese. Uma comparação das características da molécula de acetilcolina, o agonista, com as características dos derivados da xantoxilina e informações a respeito da estrutura do receptor muscarínico, bem como do desencadeamento da resposta biológica, conduzem a uma possível explicação para o efeito inibidor dos derivados da xantoxilina.

La chémoinformatique et la bioinformatique sont des disciplines devenues indispensables à la découverte de médicaments. De nos jours, les industries pharmaceutiques consacrent près de 10% de leur budget de recherche et développement, à la recherche de médicaments assisté par ordinateur (Kapetanovic 2008). Cette émergence peut s’expliquer à la fois par le développement des architectures de calculs mais aussi par le faible coup qu’engendrent des analyses in silico par rapport à des tests in-vitro.Les essais biologiques qui ont été menés depuis des décennies afin d’identifier des médicaments potentiels, commencent à former une source très importante de données et plusieurs bases de données commencent à les répertorier. La disponibilité de ce type de données a favorisé le développement d’un nouvel axe de recherche appelé la "chémogénomique" et qui s’intéresse à l’étude et à l’identification des associations possibles entre plusieurs molécules et plusieurs cibles. Ainsi, la chémogénomique permet de déterminer le profil biologique d’une molécule et nous renseigne sur sa capacité à devenir une touche intéressante mais aussi à identifier ses possibles effets indésirables. Des méthodes de chémoinformatique permettent d’utiliser ces sources de données à des fins d’apprentissage et établir des modèles prédictifs qui permettront par la suite de faire des prédictions pour connaitre l’activité d’une molécule.Cette thèse a porté sur le développement et l'utilisation de méthodes de prédictions d’association protéine-ligand. La prédiction d’une association est importante en vue d’un criblage virtuel et peut s’effectuer à l’aide de plusieurs méthodes. Au sein du laboratoire, on s’intéresse plus particulièrement au profilage de bases de données de molécules (chimiothèques) contre une série de cibles afin d’établir leur profil biologique. J’ai donc essayé au cours de ma thèse de mettre au point des modèles prédictifs d’association protéine-ligand pour un grand nombre de cibles, valider des méthodes de criblage virtuel récentes à des fins de profilage mais aussi établir un protocole de profilage automatisé, qui décide du choix de la méthode de criblage la plus adaptée en s’appuyant sur les propriétés physico-chimiques du ligand à profiler et de l’éventuelle cible. / Chemoinformatics and bioinformatics methods are now necessary in every drug discovery program. Pharmaceutical industries dedicate more than 10% of their research and development investment in computer aided drug design (Kapetanovic 2008). The emergence of these tools can be explained by the increasing availability of high performance calculating machines and also by the low cost of in silico analysis compared to in vitro tests.Biological tests that were performed over last decades are now a valuable source of information and a lot of databases are trying to list them. This huge amount of information led to the birth of a new research field called “chemogenomics”. The latter is focusing on the identification of all possible associations between all possible molecules and all possible targets. Thus, using chemogenomics approaches, one can obtain a biological profile of a molecule and even anticipate possible side effects.This thesis was focused on the development of approaches that aim to predict the binding of molecules to targets. In our lab, we focus on profiling molecular databases in order to get their full biological profile. Thus, my main work was related to this context and I tried to develop predictive models to assess the binding of ligands to proteins, to validate some virtual screening methods for profiling purpose, and finally, I developed an automatic hybrid profiling workflow that selects the best fitted virtual screening approach to use according the ligand/target context.

Submitted by Danielle Karla Martins Silva (danielle.martins@ufpe.br) on 2015-03-13T13:09:14Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) DISSERTAÇÃO Douglas Lopes Bernardo.pdf: 1660700 bytes, checksum: bbe41d2998cebacbca523ea3d1b92b7c (MD5) / Made available in DSpace on 2015-03-13T13:09:14Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) DISSERTAÇÃO Douglas Lopes Bernardo.pdf: 1660700 bytes, checksum: bbe41d2998cebacbca523ea3d1b92b7c (MD5) Previous issue date: 2014 / A avaliação do potencial carcinogênico de hidrocarbonetos policíclicos aromáticos (HPA) e seus metabólitos é realizada através de Análise de Componentes Principais (ACP) e da Relação Quantitativa da Estrutura-Atividade (QSAR) usando descritores hidrofóbico (LogP), estéreos (volume e área superficial) e eletrônicos (EAadia, μ e ΔEL-H). Os descritores eletrônicos foram obtidos com cálculos químico-quânticos do tipo AM1. O modelo de interação DNA-HPA usado é baseado na Teoria de Ressonância não sincronizada da ligação covalente (RVB) de L. Pauling, onde essa interação é descrita como uma transferência de elétron entre os orbitais de fronteira HOMO e LUMO. No estudo QSAR foram reproduzidos valores experimentais do LD50 (dose letal para matar 50% de uma população de ratos) com seis modelos matemáticos de regressão validados estatisticamente com 95% de confiança, com destaque para o modelo 4 que reproduziu com erro relativo < 1% o LD50 do antraceno, benzo[a]antraceno e benzo[a]pireno. A ACP foi refinada utilizando dados eletrônicos de metabólitos dos HPA, obtendo-se uma indicação de que são potencialmente carcinógenos, um resultado importante, uma vez que muitos dos HPA estudados estão no grupo 3 do IARC (International Agency for Research on Cancer), ou seja, não estão classificados quanto à sua carcinogenicidade, indicando que eles precisam urgentemente serem reavaliados.