Author(s)

Josué de Jesus Oliveira Araújo¹, Ricardo Morais de Miranda², Jeferson Stiver Oliveira de Castro², Antonio Florêncio de Figueiredo², Ana Cecília Barbosa Pinheiro³, Sílvia Simone dos Santos Morais⁴, Marcos Antonio Barros dos Santos⁵, Andréia de Lourdes Ribeiro Pinheiro⁶, Andréia de Lourdes Ribeiro Pinheiro⁶, Fábio dos Santos Gil¹, Heriberto Rodrigues Bitencourt⁷, Gustavo Nery Ramos Alves¹, José Ciríaco Pinheiro^1*

¹Laboratório de Química Teórica e Computacional, Universidade Federal do Pará, Belém, PA, Brasil.
²Instituto Federal de Educação, Ciência e Tecnologia do Pará, Belém, PA, Brasil.
³Universidade do Estado do Amapá, Macapá, AP, Brasil.
⁴Fundação Santa Casa de Misericórdia do Pará, Belém, PA, Brasil.
⁵Universidade do Estado do Pará, Barcarena, PA, Brasil.
⁶Departamento de Biologia, Universidade do Estado do Maranhão, São Luís, MA, Brasil.
⁷Laboratório de Síntese Organica, Universidade Federal do Pará, Belém, PA, Brasil.

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, Antimalarial Potential, Molecular Electrostatic Potential, Ligand-Heme Interaction, Multivariate Models

Araújo, J. , Miranda, R. , Castro, J. , Figueiredo, A. , Pinheiro, A. , Morais, S. , Santos, M. , Pinheiro, A. , Pinheiro, A. , Gil, F. , Bitencourt, H. , Alves, G. and Pinheiro, J. (2023) Designing Artemisinins with Antimalarial Potential, Combining Molecular Electrostatic Potential, Ligand-Heme Interaction and Multivariate Models. Computational Chemistry, 11, 1-23. doi: 10.4236/cc.2023.111001.