Submitted by Sandra Pereira (srpereira@ufrrj.br) on 2017-08-29T13:03:42Z No. of bitstreams: 1 2009 - Suzana Vieira da Silva.pdf: 1145565 bytes, checksum: cb8b708d2e722a6ccc8d9c091be5270f (MD5) / Made available in DSpace on 2017-08-29T13:03:42Z (GMT). No. of bitstreams: 1 2009 - Suzana Vieira da Silva.pdf: 1145565 bytes, checksum: cb8b708d2e722a6ccc8d9c091be5270f (MD5) Previous issue date: 2009-06-12 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior. CAPES / The Evil of Alzheimer is a disease neurodegenerativa that reaches to the cognitive functions among them the memory, attention and learning. The main strategy used for his/her treatment is addressed in the search of improving the hipofun??o colin?rgica, inhibiting the enzyme acetylcholinesterase, so that the acetylcholine can stay more available in the rift sin?ptica for the accomplishments of the sinapses, since this enzyme has the hidrolisar function the acetylcholine. The nature offers an enormous variety of substances used as f?rmacos and the sea sponges has been demonstrating be rich in these substances. They were extracted of the sponge Plakortis angulospiculatus three polyketides that through the method Ellman demonstrated activity anticolinester?sica. Through techniques of Molecular Modelling, calculations semiempiricos were accomplished using the method PM3 to analyze the geometric interactions and energies involved in the compound polyketidesacetylcholinesterase with the objective of analyzing a possible use of these as f?rmacos for the Evil of Alzheimer. As if he/she didn't know the state in that the ranch would be (with Ser200 and neutral His440 or no) in the moment of the interaction, calculations were accomplished for the three polyketides in both ranches. Studies with inhibitors already known tacrina and huprina X (both neutral one and protonadas) they were also accomplished at both ranches in order to comparison. Resulted obtained he in this work showed the reliability of the employed method, likewise as values of favorable entalpia for the formation of all the compounds independent pollyketide-acetylcholinesterase of the ranch. It was observed by the energy values a preference when the same ones if they found in the ranch protonado diferencialmente of the inhibitors tacrina and huprina X that independent of his/her state (protonados or no) they showed better interaction for the neutral ranch. The calculations accomplished for the tacrina demonstrated that even after optimization the main interactions described already by the literature stayed and that possibly she meets protonada inside of the seen ranch the values of energy found for this structure. The huprina X that is a hybrid of the tacrina with the huperzina A it showed HER likewise the most significant interactions as the more favorable energy values, what is in agreement with the high constant of inhibition of 26pM found in the literature for human's acetilcolinesterase. Before the obtained data we can end that the polyketides in spite of they obtain favorable energy values the formation of the compound polyketide-acetylcholinesterase these values are not competitive with the energy values found for the inhibitors tacrina and huprina X. however, in the production of a f?rmaco they are not taken into account just energy interactions and as the tacrina it already demonstrated to possess high hepatic toxicity, besides adverse reactions as nausea and vomit, the polyketides for they be natural substance were able to in this case be competitive if they demonstrated to possess softer adverse reactions. / O Mal de Alzheimer ? uma doen?a neurodegenerativa que atinge ?s fun??es cognitivas entre elas a mem?ria, aten??o e aprendizagem. A principal estrat?gia utilizada para seu tratamento est? direcionado na busca de melhorar a hipofun??o colin?rgica, inibindo a enzima acetilcolinesterase, para que a acetilcolina possa permanecer mais dispon?vel na fenda sin?ptica para as realiza??es das sinapses, j? que esta enzima tem a fun??o de hidrolisar a acetilcolina. A natureza oferece uma enorme variedade de subst?ncias utilizadas como f?rmacos e as esponjas marinhas tem demonstrado serem ricas nestas subst?ncias. Foram extra?dos da esponja Plakortis angulospiculatus tr?s policet?deos que atrav?s do m?todo Ellman demonstraram atividade anticolinester?sica. Atrav?s de t?cnicas de Modelagem Molecular, foram realizados c?lculos semiempiricos utilizando o m?todo PM3 para analisar as intera??es geom?tricas e energias envolvidas no complexo policet?deos-acetilcolinesterase com o objetivo de analisar uma poss?vel utiliza??o destes como f?rmacos para o Mal de Alzheimer. Como n?o se conhecia o estado em que o s?tio se encontraria (com a Ser200 e His440 neutros ou n?o) no momento da intera??o, foram realizados c?lculos para os tr?s policet?deos em ambos os s?tios. Estudos com inibidores j? conhecidos tacrina e huprina X (ambas neutra e protonadas) tamb?m foram realizados em ambos os s?tios a fim de compara??o. O resultados obtidos neste trabalho mostraram a confiabilidade do m?todo empregado, assim tamb?m como valores de entalpia favor?veis para a forma??o de todos os complexos policet?deo-acetilcolinesterase independente do s?tio. Observou-se pelos valores energ?ticos uma prefer?ncia quando os mesmos se encontravam no s?tio protonado diferencialmente dos inibidores tacrina e huprina X que independente do seu estado (protonados ou n?o) mostraram melhor intera??o pelo s?tio neutro. Os c?lculos realizados para a tacrina demonstraram que mesmo ap?s otimiza??o as principais intera??es j? descritas pela literatura se mantiveram e que possivelmente ela se encontra protonada dentro do s?tio visto os valores de energia encontrados para esta estrutura. A huprina X que ? um h?brido da tacrina com a huperzina A mostrou as intera??es mais significativas assim tamb?m como os valores energ?ticos mais favor?veis, o que est? de acordo com a alta constante de inibi??o de 26pM encontrados na literatura para a acetilcolinesterase de humano. Diante dos dados obtidos podemos concluir que os policet?deos apesar de obterem valores energ?ticos favor?veis a forma??o do complexo policet?deo-acetilcolinesterase estes valores n?o s?o competitivos com os valores energ?ticos encontrados para os inibidores tacrina e huprina X. No entanto, na fabrica??o de um f?rmaco n?o s?o levados em conta apenas intera??es energ?ticas e como a tacrina j? demonstrou possuir alta toxicidade hep?tica, al?m de rea??es adversas como n?usea e v?mito, os policet?deos por serem subst?ncia naturais poderiam neste caso ser competitivos se demonstrassem possuir rea??es adversas mais brandas.