Revisiting Plasmodium falciparum P-type ATPase 4 in malarial: ADMET, mutation effect, and molecular simulation...

Malaria, a life-threatening disease caused by Plasmodium parasites, remains a major global health concern, with 247 million cases and approximately 627,000 deaths reported in 2020 across 84 malaria-endemic countries. The Plasmodium falciparum P-type ATPase 4 (PfATP4) gene is expressed throughout the parasite's asexual erythrocytic cycle and plays a vital role in regulating sodium ion levels in the plasma membrane. This study aimed to computationally evaluate selected clinical candidate compounds targeting PfATP4, focusing on their pharmacokinetics and molecular binding characteristics to support further drug development. Pharmacokinetic analyses revealed that Concanamycin A, Maduramicin, and GNF-Pf4492 exhibit low gastrointestinal absorption, while Brefeldin A, MMV396719, MMV006239, and Cipargamin can cross the blood-brain barrier. Among these, Brefeldin A and MMV006239 showed the lowest toxicity. Molecular docking revealed that (+)-SJ733 had the highest binding affinity (-8.891 kcal/mol), followed by MMV665878 (-7.796 kcal/mol) and Maduramicin (-7.791 kcal/mol). All 11 compounds showed binding affinities below -7.000 kcal/mol. Molecular dynamics simulations indicated stable interactions between PfATP4 and both (+)-SJ733 and MMV665878, involving key residues such as PHE917, GLN921, ARG985, and THR993. MMGBSA analysis showed that the MMV665878-PfATP4 complex was more stable and energetically favorable than the (+)-SJ733-PfATP4 complex under simulated physiological conditions. In conclusion, (+)-SJ733 and MMV665878 demonstrate strong potential as PfATP4 inhibitors, with different interaction profiles. Further in vivo and pharmacometric studies are required to validate their efficacy and determine optimal dosing strategies for malaria treatment.