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Master's Dissertation
DOI
10.11606/D.9.2017.tde-18102017-152832
Document
Author
Full name
João Paulo Machado Martins
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2017
Supervisor
Committee
Trossini, Gustavo Henrique Goulart (President)
Honorio, Káthia Maria
Nakaya, Helder Takashi Imoto
Scott, Luis Paulo Barbour
Title in Portuguese
Triagem virtual de inibidores da enzima di-hidrofolato redutase de Schistosoma mansoni (SmDHFR)
Keywords in Portuguese
Acoplamento Molecular
Di-hidrofolato Redutase
GRID/PCA
Planejamento de Fármacos Baseado na Estrutura do Receptor (SBDD)
Schistosoma mansoni
Abstract in Portuguese
A esquistossomose é uma das principais causas de morbidade em países Tropicais e Subtropicais, gerando graves consequências socioeconômicas. Atualmente, os fármacos disponíveis para o tratamento da desta doença são praziquantel e oxamniquina, porém relatos de baixa susceptibilidade do parasita a esses medicamentos sugerem a necessidade de novas estratégias terapêuticas para o tratamento da doença. Todavia, existe pouco interesse da indústria farmacêutica no desenvolvimento de fármacos contra doenças tropicais e negligenciadas, entre as quais se encontra a esquistossomose. Devido a estes fatores, o presente trabalho teve por objetivo geral utilizar ferramentas computacionais para identificar inibidores da SmDHFR candidatos a novos fármacos. Avaliou-se as características exclusivas para a proteína de S. mansoni por meio de uma análise das sequências FASTA em comparação com a DHFR de outros organismos. A fim de garantir a ação seletiva dessas moléculas frente a enzima do parasita, os campos moleculares de interação seletivos para SmDHFR foram calculados e empregados na construção do modelo farmacofórico, o qual foi utilizado na triagem virtual de inibidores de SmDHFR. Os estudos computacionais realizados nos permitiram a seleção de 20 moléculas com uma boa complementariedade com o modelo farmacofórico gerado e com potencial para serem inibidores de SmDHFR.
Title in English
Virtual screening of dihydrofolate reductase Schistosoma mansoni (SmDHFR) enzyme inhibitors.
Keywords in English
Dihydrofolate Reductase
GRID / PCA
Molecular coupling
Schistosoma mansoni
Structure Based Drug Design (SBDD)
Abstract in English
Schistosomiasis is one of morbidity's main causes in tropical and subtropical countries, which leads to serious socioeconomic consequences. Praziquantel and oxamniquina are the drugs currently available for treating this disease, but reports points that the parasite has been resistant to both drugs, which suggests the need for new therapeutic strategies for the treatment of this disease. However, there is little interest in the pharmaceutical industry in developing drugs against neglected tropical diseases, including schistosomiasis. Due to these factors, the present work has the general objective to use computational tools to identify SmDHFR inhibitors which could be good candidates for developing new drugs. Evaluation of the exclusive characteristics of the S. mansoni protein were performed by FASTA sequence analyses in comparison to DHFR from other organisms. In order to guarantee the selective action of these molecules against the parasite enzyme, the molecular interaction fields selective for SmDHFR were calculated and used in the construction of the pharmacophoric model, which was further used in the virtual screening of SmDHFR inhibitors. Computational studies were performed and those led us to 20 molecules with a good complementarity with the pharmacophoric model that was previously generated and with potential to be SmDHFR inhibitors.
 
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Publishing Date
2017-10-31
 
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