Structure-based drug design studies of the interactions ofent-kaurane diterpenes derived from Wedelia paludosa with the Plasmodium falciparumsarco/endoplasmic reticulum Ca2+-ATPase PfATP6

Abstract

Malaria is responsible for more deaths around the world than any other parasitic disease. Due to the emergence of strains that are resistant to the current chemotherapeutic antimalarial arsenal, the search for new antimalarial drugs remains urgent though hampered by a lack of knowledge regarding the molecular mechanisms of artemisinin resistance. Semisynthetic compounds derived from diterpenes from the medicinal plant Wedelia paludosa were tested in silico against the Plasmodium falciparum Ca2+-ATPase, PfATP6. This protein was constructed by comparative modelling using the three-dimensional structure of a homologous protein, 1IWO, as a scaffold. Compound 21 showed the best docking scores, indicating a better interaction with PfATP6 than that of thapsigargin, the natural inhibitor. Inhibition of PfATP6 by diterpene compounds could promote a change in calcium homeostasis, leading to parasite death. These data suggest PfATP6 as a potential target for the antimalarial ent-kaurane diterpenes.

Successful application of virtual screening and molecular dynamics simulations against antimalarial molecular targets

“…MD simulation of the Tx001-PfATP6 complex - Initially, the previously built PfATP6 model (Guimarães et al 2015) was evaluated by RMSD, a visual inspection of the binding site, Ramachandran plot, and ANOLEA. As a result, PfATP6 was built using 2O9J, 3BA6, and 1IWO as templates, with 43%, 49%, and 43.5% identity, respectively (Fig.…”

“…The 3-D structures were retrieved with PDB codes 2ANL, 1LF3, and 3BPF with resolutions of 3.30, 2.70, and 2.90 Å, respectively. PfATP6 was obtained using a previous comparative modelling method (Guimarães et al 2015). Next, the target protonation state was adjusted to pH 4.0 for plasmepsin-II, plasmepsin-IV, and falcipain-II to simulate the food vacuole environment.…”

“…Molecular dynamics (MD) simulation of the Tx001-PfATP6 complex - Initially, the previously built model (Guimarães et al 2015) was evaluated using the Ramachandran plot implemented on Procheck software and Assessing Protein Structures with a Non-local Atomic Interaction Energy (ANOLEA; Melo & Feytmans 1998). The Ramachandran plot and ANOLEA evaluate structural and packing quality, respectively.…”

“…Thus, the pyrazol derivative’s anticancer activity motivated us to perform VS against P. falciparum molecular targets present in the OOMT. Four antimalarial molecular targets were included in the OOMT, including plasmepsin-IV (PDB: 2ANL), plasmepsin-II (PDB: 1LF3), falcipain-II (PDB: 3BPF), and the PfATP6 model (Guimarães et al 2015). …”

A Comprehensive View on (−)‐7‐Oxo‐ent‐kaur‐16‐en‐19‐oic Acid, the Major Constituent of Xylopia sericea Leaves Extract: Complete NMR Assignments, X‐Ray Crystallographic Structure, in Vitro Antimalarial Activity and Cytotoxicity

“…[5] Against this backdrop, it is clear that the discovery of new antimalarial drugs is of high relevance and screening of natural products as well as of plant extracts remains as a valid approach. Our previous results on the antimalarial activity of kaurane derivatives [6,7] have motivated the evaluation of Xylopia sericea A.ST.-HIL. (Annonaceae) leaves dichloromethane extract that was shown to be active against chloroquine-resistant P. falciparum (W2 strain).…”