Please use this identifier to cite or link to this item: http://repositorio.ufla.br/jspui/handle/1/11257
Title: Inovação do método MIA-QSAR: aplicação para doenças tropicais negligenciadas
Other Titles: Innovation of the MIA-QSAR method: application to neglected tropical diseases
Authors: Freitas, Matheus Puggina de
Rocha, Denise Alvarenga
Mancini, Daiana Teixeira
Guimarães, Luiz Gustavo de Lima
Ramalho, Teodorico de Castro
Keywords: aug-MIA-QSAR
aug-MIA-QSARcolor
PLS
MLR
Análise multivariada de imagens
Doenças negligenciadas
Multivariate image analysis
Neglected diseases
Issue Date: 14-Jun-2016
Publisher: Universidade Federal de Lavras
Citation: DUARTE, M. H. Inovação do método MIA-QSAR: aplicação para doenças tropicais negligenciadas. 2016. 165 p. Tese (Doutorado em Agroquímica)-Universidade Federal de Lavras, Lavras, 2016.
Abstract: Multivariate image analysis applied to the quantitative structure-activity relationships (MIA-QSAR) is a 2D QSAR technique that has been presenting promising outcomes for the development of new drug candidates, due to its simplicity, rapidity and low cost. In this way, the present study aims at introducing, consolidating and improving the new dimensions named aug-MIA-QSAR and aug-MIA-QSARcolor, as well as applying them to the study of neglected diseases, in order to obtain new drug targets using chemico-biological interpretation of the MIA molecular descriptors. Four compound data sets with experimental bioactivities against Chagas disease, malaria, dengue and schistosomiasis were evaluated using three approaches: MIA-QSARt, aug-MIA-QSAR and aug-MIA-QSARcolor. In general, representations of atoms as spheres with different colors and sizes proportional to the corresponding van der Waals radii (aug-MIA approaches) improved the predictive ability and interpretability in all data sets. The use of colors proportional to the Pauling´s electronegativity showed that MIA descriptors are capable of identifying periodic properties relevant for the studied activity. Finally, solid colors instead of spotlighted atoms allowed a correct identification of atoms by means of pixel values in the studies for malaria, dengue and schistosomiasis, which were, subsequently, useful for the chemical interpretation related to the bioactivity. It can be inferred that semicarbazones and thiosemicarbazones derivative with a tri-substituted ring in R1 group and a trifluoro methyl group in the R 3 position instead of a chlorine antitripanossoma resulted in higher activity. The antimalarial activity of quinolon-4(1H)imines can be improved if: 1) R1 and R2 are electron donor groups, 2) R3 has long aminoalkyl chains, and 3) R4 possesses substituents with big atomic volume. In the study for dengue, it was found that tetrapeptides with unbranched small size amino acids in the A1 and A4 positions can increase the substrate affinity (Km) to the NS3 protein, and when in A1 and A2 positions, the substrate cleavage rate (kcat). On the other hand, acidic amino acids in the A2 and A4 positions were found to be related with low substrate affinity to the NS3 protein and when present in A1, with low substrate cleavage rate. Finally, the presence of metoxy substituents in R1 (or R2) and R5 in the neolignan backbone can favor their antischistosomal activity.
URI: http://repositorio.ufla.br/jspui/handle/1/11257
Appears in Collections:Agroquímica - Doutorado (Teses)

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