Desenvolvimento de um Modelo Emp?rico de Predi??o da Atividade de Inibidores da Urease utilizando o M?todo Semi-Emp?rico PM6
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| Data de Publicação: | 2014 |
| Tipo de documento: | Dissertação |
| Idioma: | por |
| Título da fonte: | Biblioteca Digital de Teses e Dissertações da UFRRJ |
| Texto Completo: | https://tede.ufrrj.br/jspui/handle/jspui/4163 |
Resumo: | Urease is an important enzyme for the research in agriculture, environment and medicine. This enzyme catalyzes the hydrolysis of urea to ammonia and carbamate, which decomposes spontaneously, yielding a second molecule of ammonia, causing a significant increase of pH solution. In order to develop theoretical models for the prediction of activities of urease inhibitors, we initially studied the enzyme?s spin multiplicity, which contains two Ni(II) ?ons, and the state of protonation of the oxygen located between the nickel ions. The results indicate that the system is best represented by the triplet or quintet state and the oxygen atom located between the nickel ions, probably is a hydroxyl ion. Based on these results, the construction of the models was based on literature proposals about the use of thermodynamic cycles for the calcultation of the free energy of binding between ligands and enzymes. In the present work, parameters such as the interaction enthalpy, the Gibbs free energy required for the inhibitor to go from the aqueous phase to the interior of the enzyme and the entropic losses associated to the freezing of bonds after the binding of the inhibitors to the enzyme were used to develop correlations with the measured experimental Ki values. The quantification of these parameters for some phosphinic acids derivatives from the literature allowed us to obtain a good empirical model for the correlation between experimental activity data and the theoretical parameters (r=0.92). The model was employed for the prediction of the relative activity of a series of new proposed compounds by the organophosphorous synthesis group of UFRRJ. It was possible to identify which compounds are the most promising and which are the main factors that should be modified in order to optimize the urease inhibition profile by these compounds. |
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Sant'Anna, Carlos Mauricio Rabello de827232227-72http://lattes.cnpq.br/2087099684752643Bauerfeldt, Glauco FavillaMachado, S?rgio de Paula122348897-74http://lattes.cnpq.br/4206525243279971Rocha, Sheisi Fonseca Leite da Silva2020-11-19T13:29:49Z2014-04-15Rocha, Sheisi Fonseca Leite da Silva. Desenvolvimento de um modelo emp?rico de predi??o da atividade de inibidores da Urease utilizando o m?todo Semi-Emp?rico PM6. 2014. [73 f.]. Disserta??o (Programa de P?s-Gradua??o em Qu?mica) - Universidade Federal Rural do Rio de Janeiro, [Serop?dica - RJ] .https://tede.ufrrj.br/jspui/handle/jspui/4163Urease is an important enzyme for the research in agriculture, environment and medicine. This enzyme catalyzes the hydrolysis of urea to ammonia and carbamate, which decomposes spontaneously, yielding a second molecule of ammonia, causing a significant increase of pH solution. In order to develop theoretical models for the prediction of activities of urease inhibitors, we initially studied the enzyme?s spin multiplicity, which contains two Ni(II) ?ons, and the state of protonation of the oxygen located between the nickel ions. The results indicate that the system is best represented by the triplet or quintet state and the oxygen atom located between the nickel ions, probably is a hydroxyl ion. Based on these results, the construction of the models was based on literature proposals about the use of thermodynamic cycles for the calcultation of the free energy of binding between ligands and enzymes. In the present work, parameters such as the interaction enthalpy, the Gibbs free energy required for the inhibitor to go from the aqueous phase to the interior of the enzyme and the entropic losses associated to the freezing of bonds after the binding of the inhibitors to the enzyme were used to develop correlations with the measured experimental Ki values. The quantification of these parameters for some phosphinic acids derivatives from the literature allowed us to obtain a good empirical model for the correlation between experimental activity data and the theoretical parameters (r=0.92). The model was employed for the prediction of the relative activity of a series of new proposed compounds by the organophosphorous synthesis group of UFRRJ. It was possible to identify which compounds are the most promising and which are the main factors that should be modified in order to optimize the urease inhibition profile by these compounds.A urease ? uma enzima importante para as pesquisas relacionadas com a agricultura, meio ambiente e medicina. Ela catalisa a rea??o de hidr?lise da ur?ia para formar am?nia e carbamato, o qual se decomp?e espontaneamente, produzindo uma segunda mol?cula de am?nia e di?xido de carbono, provocando um significativo aumento do pH da solu??o. Com o objetivo de desenvolver modelos de predi??o da atividade de inibidores da urease, estudou-se inicialmente a multiplicidade de spin da enzima, que cont?m dois ?ons Ni(II), e o estado de protona??o do oxig?nio localizado entre estes ?ons. Os resultados indicaram que o sistema ? melhor representado pelo estado tripleto ou quinteto e o oxig?nio localizado entre os ?ons de n?quel provavelmente ? um ?on hidroxila. A partir destes resultados, a constru??o dos modelos se baseou em propostas da literatura sobre o uso de ciclos termodin?micos para se calcular a energia livre de intera??o entre ligantes e enzimas. No presente estudo, foram combinados termos referentes ? entalpia de intera??o entre o inibidor e a enzima, a energia livre de Gibbs necess?ria para o inibidor passar do meio aquoso para o interior da enzima e as perdas entr?picas devido a restri??es rotacionais ap?s a intera??o do mesmo com a enzima para se obter fun??es de correla??o com constantes inibit?rias (Ki) obtidas experimentalmente. A quantifica??o destes par?metros para alguns derivados do ?cido fosf?nico da literatura nos possibilitou o desenvolvimento de um modelo para determina??o da atividade com boa correla??o com dados experimentais (r=0,92). Este modelo foi utilizado na predi??o da atividade relativa de novas dialquilfosforilidrazonas, sintetizadas pelo grupo de s?ntese de organofosforados da UFRRJ. Foi poss?vel identificar quais compostos s?o os mais promissores da s?rie proposta e quais fatores devem ser alterados para otimizar o perfil de inibi??o da urease.Submitted by Sandra Pereira (srpereira@ufrrj.br) on 2020-11-19T13:29:49Z No. of bitstreams: 1 2014 - Sheisi Fonseca Leite da Silva Rocha.pdf: 988981 bytes, checksum: 49abe58d9422ae29356979cf6629dec8 (MD5)Made available in DSpace on 2020-11-19T13:29:49Z (GMT). No. of bitstreams: 1 2014 - Sheisi Fonseca Leite da Silva Rocha.pdf: 988981 bytes, checksum: 49abe58d9422ae29356979cf6629dec8 (MD5) Previous issue date: 2014-04-15Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior, CAPES, Brasil.application/pdfhttps://tede.ufrrj.br/retrieve/63070/2014%20-%20Sheisi%20Fonseca%20Leite%20da%20Silva%20Rocha.pdf.jpgporUniversidade Federal Rural do Rio de JaneiroPrograma de P?s-Gradua??o em Qu?micaUFRRJBrasilInstituto de Ci?ncias ExatasABRAHAM, D. J. Burger?s: medicinal chemistry and drug discovery. 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| dc.title.por.fl_str_mv |
Desenvolvimento de um Modelo Emp?rico de Predi??o da Atividade de Inibidores da Urease utilizando o M?todo Semi-Emp?rico PM6 |
| title |
Desenvolvimento de um Modelo Emp?rico de Predi??o da Atividade de Inibidores da Urease utilizando o M?todo Semi-Emp?rico PM6 |
| spellingShingle |
Desenvolvimento de um Modelo Emp?rico de Predi??o da Atividade de Inibidores da Urease utilizando o M?todo Semi-Emp?rico PM6 Rocha, Sheisi Fonseca Leite da Silva Organofosforados Modelo de energia livre M?todo semi-emp?rico Urease Organophosphorus compounds Free energy models Semi-empirical method Qu?mica |
| title_short |
Desenvolvimento de um Modelo Emp?rico de Predi??o da Atividade de Inibidores da Urease utilizando o M?todo Semi-Emp?rico PM6 |
| title_full |
Desenvolvimento de um Modelo Emp?rico de Predi??o da Atividade de Inibidores da Urease utilizando o M?todo Semi-Emp?rico PM6 |
| title_fullStr |
Desenvolvimento de um Modelo Emp?rico de Predi??o da Atividade de Inibidores da Urease utilizando o M?todo Semi-Emp?rico PM6 |
| title_full_unstemmed |
Desenvolvimento de um Modelo Emp?rico de Predi??o da Atividade de Inibidores da Urease utilizando o M?todo Semi-Emp?rico PM6 |
| title_sort |
Desenvolvimento de um Modelo Emp?rico de Predi??o da Atividade de Inibidores da Urease utilizando o M?todo Semi-Emp?rico PM6 |
| author |
Rocha, Sheisi Fonseca Leite da Silva |
| author_facet |
Rocha, Sheisi Fonseca Leite da Silva |
| author_role |
author |
| dc.contributor.advisor1.fl_str_mv |
Sant'Anna, Carlos Mauricio Rabello de |
| dc.contributor.advisor1ID.fl_str_mv |
827232227-72 |
| dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/2087099684752643 |
| dc.contributor.referee1.fl_str_mv |
Bauerfeldt, Glauco Favilla |
| dc.contributor.referee2.fl_str_mv |
Machado, S?rgio de Paula |
| dc.contributor.authorID.fl_str_mv |
122348897-74 |
| dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/4206525243279971 |
| dc.contributor.author.fl_str_mv |
Rocha, Sheisi Fonseca Leite da Silva |
| contributor_str_mv |
Sant'Anna, Carlos Mauricio Rabello de Bauerfeldt, Glauco Favilla Machado, S?rgio de Paula |
| dc.subject.por.fl_str_mv |
Organofosforados Modelo de energia livre M?todo semi-emp?rico |
| topic |
Organofosforados Modelo de energia livre M?todo semi-emp?rico Urease Organophosphorus compounds Free energy models Semi-empirical method Qu?mica |
| dc.subject.eng.fl_str_mv |
Urease Organophosphorus compounds Free energy models Semi-empirical method |
| dc.subject.cnpq.fl_str_mv |
Qu?mica |
| description |
Urease is an important enzyme for the research in agriculture, environment and medicine. This enzyme catalyzes the hydrolysis of urea to ammonia and carbamate, which decomposes spontaneously, yielding a second molecule of ammonia, causing a significant increase of pH solution. In order to develop theoretical models for the prediction of activities of urease inhibitors, we initially studied the enzyme?s spin multiplicity, which contains two Ni(II) ?ons, and the state of protonation of the oxygen located between the nickel ions. The results indicate that the system is best represented by the triplet or quintet state and the oxygen atom located between the nickel ions, probably is a hydroxyl ion. Based on these results, the construction of the models was based on literature proposals about the use of thermodynamic cycles for the calcultation of the free energy of binding between ligands and enzymes. In the present work, parameters such as the interaction enthalpy, the Gibbs free energy required for the inhibitor to go from the aqueous phase to the interior of the enzyme and the entropic losses associated to the freezing of bonds after the binding of the inhibitors to the enzyme were used to develop correlations with the measured experimental Ki values. The quantification of these parameters for some phosphinic acids derivatives from the literature allowed us to obtain a good empirical model for the correlation between experimental activity data and the theoretical parameters (r=0.92). The model was employed for the prediction of the relative activity of a series of new proposed compounds by the organophosphorous synthesis group of UFRRJ. It was possible to identify which compounds are the most promising and which are the main factors that should be modified in order to optimize the urease inhibition profile by these compounds. |
| publishDate |
2014 |
| dc.date.issued.fl_str_mv |
2014-04-15 |
| dc.date.accessioned.fl_str_mv |
2020-11-19T13:29:49Z |
| dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
| dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
| format |
masterThesis |
| status_str |
publishedVersion |
| dc.identifier.citation.fl_str_mv |
Rocha, Sheisi Fonseca Leite da Silva. Desenvolvimento de um modelo emp?rico de predi??o da atividade de inibidores da Urease utilizando o m?todo Semi-Emp?rico PM6. 2014. [73 f.]. Disserta??o (Programa de P?s-Gradua??o em Qu?mica) - Universidade Federal Rural do Rio de Janeiro, [Serop?dica - RJ] . |
| dc.identifier.uri.fl_str_mv |
https://tede.ufrrj.br/jspui/handle/jspui/4163 |
| identifier_str_mv |
Rocha, Sheisi Fonseca Leite da Silva. Desenvolvimento de um modelo emp?rico de predi??o da atividade de inibidores da Urease utilizando o m?todo Semi-Emp?rico PM6. 2014. [73 f.]. Disserta??o (Programa de P?s-Gradua??o em Qu?mica) - Universidade Federal Rural do Rio de Janeiro, [Serop?dica - RJ] . |
| url |
https://tede.ufrrj.br/jspui/handle/jspui/4163 |
| dc.language.iso.fl_str_mv |
por |
| language |
por |
| dc.relation.references.por.fl_str_mv |
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