TITLE:
Designing Artemisinins with Antimalarial Potential, Combining Molecular Electrostatic Potential, Ligand-Heme Interaction and Multivariate Models
AUTHORS:
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
KEYWORDS:
Artemisinins, Antimalarial Potential, Molecular Electrostatic Potential, Ligand-Heme Interaction, Multivariate Models
JOURNAL NAME:
Computational Chemistry,
Vol.11 No.1,
December
1,
2022
ABSTRACT: 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.