摘要
Artemisinins tested against W-2 strains of malaria falciparum are investigated with molecular electrostatic potential (MEP), in an attempt to identify key features of the compounds that are necessary for their activities, as well as to investigate likely interactions with the receptor in a biological process and to use that information to propose new molecules. In order to discover the best geometry involving the ligand-receptor complexes (heme) studied and help in the proposition of the new derivatives, molecular simulations of interactions between the most negative charged region around the peroxide and heme locates (the ones around the Fe2+ ion) were carried out. In addition, PCA (principal components analysis), HCA (hierarchical cluster analysis), SDA (stepwise discriminant analysis), and KNN (K-nearest neighbor) multivariate models were employed to investigate which descriptors are responsible for the classification between the higher and lower antimalarial activity of the compounds, and also this information was used to propose new potentially active molecules. The information accumulated in studies of MEP, molecular docking, and multivariate analysis supported the proposal of new structures with potential antimalarial activities. The multivariate models constructed were applied to the new structures and indicated numbers 19 and 20 as the most prominent for syntheses and biological assays.
Artemisinins tested against W-2 strains of malaria falciparum are investigated with molecular electrostatic potential (MEP), in an attempt to identify key features of the compounds that are necessary for their activities, as well as to investigate likely interactions with the receptor in a biological process and to use that information to propose new molecules. In order to discover the best geometry involving the ligand-receptor complexes (heme) studied and help in the proposition of the new derivatives, molecular simulations of interactions between the most negative charged region around the peroxide and heme locates (the ones around the Fe2+ ion) were carried out. In addition, PCA (principal components analysis), HCA (hierarchical cluster analysis), SDA (stepwise discriminant analysis), and KNN (K-nearest neighbor) multivariate models were employed to investigate which descriptors are responsible for the classification between the higher and lower antimalarial activity of the compounds, and also this information was used to propose new potentially active molecules. The information accumulated in studies of MEP, molecular docking, and multivariate analysis supported the proposal of new structures with potential antimalarial activities. The multivariate models constructed were applied to the new structures and indicated numbers 19 and 20 as the most prominent for syntheses and biological assays.
作者
Josué de Jesus Oliveira Araújo
Ricardo Morais de Miranda
Jeferson Stiver Oliveira de Castro
Antonio Florêncio de Figueiredo
Ana Cecília Barbosa Pinheiro
Sílvia Simone dos Santos Morais
Marcos Antonio Barros dos Santos
Andréia de Lourdes Ribeiro Pinheiro
Andréia de Lourdes Ribeiro Pinheiro
Fábio dos Santos Gil
Heriberto Rodrigues Bitencourt
Gustavo Nery Ramos Alves
José Ciríaco Pinheiro
Josué de Jesus Oliveira Araújo;Ricardo Morais de Miranda;Jeferson Stiver Oliveira de Castro;Antonio Florêncio de Figueiredo;Ana Cecília Barbosa Pinheiro;Sílvia Simone dos Santos Morais;Marcos Antonio Barros dos Santos;Andréia de Lourdes Ribeiro Pinheiro;Andréia de Lourdes Ribeiro Pinheiro;Fábio dos Santos Gil;Heriberto Rodrigues Bitencourt;Gustavo Nery Ramos Alves;José Ciríaco Pinheiro(Laboratório de Química Teórica e Computacional, Universidade Federal do Pará, Belém, PA, Brasil;Instituto Federal de Educação, Ciência e Tecnologia do Pará, Belém, PA, Brasil;Universidade do Estado do Amapá, Macapá, AP, Brasil;Fundação Santa Casa de Misericórdia do Pará, Belém, PA, Brasil;Universidade do Estado do Pará, Barcarena, PA, Brasil;Departamento de Biologia, Universidade do Estado do Maranhão, São Luís, MA, Brasil;Laboratório de Síntese Organica, Universidade Federal do Pará, Belém, PA, Brasil)