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Master's Dissertation
DOI
https://doi.org/10.11606/D.75.2021.tde-31052021-104513
Document
Author
Full name
Felipe Marçal Morgantini
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Carlos, 2021
Supervisor
Committee
Leitão, Andrei (President)
Silva, Albérico Borges Ferreira da
Albuquerque, Magaly Girão
Giuliatti, Silvana
Title in Portuguese
Análise quimiométrica de seletividade nos sítios ativos de cisteíno proteases da família da papaína para o estudo de substâncias antiparasitárias e antineoplásicas
Keywords in Portuguese
análise de componentes principais (PCA)
campos de interação molecular (MIF)
cisteíno catepsinas
cruzaína
docagem molecular
ensaio virtual baseado no alvo macromolecular (SBVS)
hibridização molecular (HM)
quimioinformática
Abstract in Portuguese
Entre as enzimas pesquisadas pelo Grupo de Química Medicinal e Biológica NEQUIMED estão as cisteíno proteases (CP), especialmente as envolvidas em doenças negligenciadas, e.g. doença de Chagas, endêmica na América Latina, e Leishmaniose, endêmica em 83 países (forma visceral) incluindo o Brasil. As CP envolvidas neste trabalho pertencem a família da papaína: cruzaína do Trypanosoma Cruzi e catepsinas humanas: B, K, L e S. Por serem alvos terapêuticos de diversas patologias a inibição destas proteases é bastante pesquisada. A alta similaridade na sequência de aminoácidos torna a seletividade um desafio. Considerando a grande disponibilidade de estruturas cristalográficas depositadas, a abordagem computacional adotada foi a utilização de descritores tridimensionais: campos de interação molecular, onde o mapeamento energético é obtido através da interação intermolecular entre sondas químicas e proteína no sítio ativo, que é usado como variáveis na análise de componentes principais, o qual destacou regiões seletivas, racionalizando a busca de grupos químicos com propriedades similares ao modelo farmacofórico obtido. O espaço químico de busca utilizado foi delimitado por inibidores dipeptidil nitrila com elevada potência disponíveis na base de moléculas ChEMBL. A complementaridade química dos compostos selecionados foram analisados após docagem molecular para a seleção de substituintes químicos que foram utilizados como blocos construtores no planejamento de estruturas baseado no ligante denominado hibridização molecular, buscando aliar seletividade e potência farmacodinâmica nos compostos planejados.
Title in English
Chemometric analysis of selectivity in the active sites of cysteine proteases of the papain family for the study of antiparasitic and antineoplastic substances
Keywords in English
chemoinformatics
cruzain
molecular hybridization (MH)
molecular docking
molecular interaction field (MIF)
partial components analysis (PCA)
structure-based virtual screen (SBVS), cysteine cathepsin
Abstract in English
Among the enzymes researched by the Medicinal and Biological Chemistry Group NEQUIMED are cysteine proteases (CP), especially those involved in neglected diseases, eg Chagas disease, endemic in Latin America, and Leishmaniasis, endemic in 83 countries (visceral form) including Brazil. The PCs involved in this work belong to the papain family: cruzain from Trypanosoma Cruzi and human cathepsins: B, K, L and S. Since they are therapeutic targets for several pathologies, the inhibition of these proteases is intensively researched. The high similarity in the amino acid sequence makes selectivity a challenge. Considering the great availability of deposited crystallographic structures, the in silico approach adopted was the use of three-dimensional descriptors: molecular interaction fields, where the energy mapping is obtained through the intermolecular interaction between chemical probes and protein in the active site, that is used as variables in principal component analysis, which highlighted selective regions, rationalizing the search for chemical groups with properties similar to the pharmacophoric model obtained. The chemical search space used was limited by dipeptidyl nitrile inhibitors with high potency available on ChEMBL database. The chemical complementarity of the selected compounds was analyzed after molecular docking for the selection of chemical substituents that were used as building blocks in ligand-based drug design approach called molecular hybridization, seeking to combine selectivity and pharmacodynamic potency in the planned compounds.
 
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Publishing Date
2021-06-01
 
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