Molecular docking, MD simulation, and MMGBSA-binding free energy estimation study identify antibiotic analogs as potential antimalarials targeting housekeeping proteins of Plasmodium falciparum apicoplast

Abstract

ABSTRACT Plasmodium falciparum exclusively harbours a non-photosynthetic plastid-like organelle called ‘apicoplast,’ crucial for survival. The apicoplast genome resembles chloroplasts, albeit much reduced at 35 kb. The housekeeping functions of the apicoplast are similar to prokaryotes, and several antibiotics have been reported to kill the malaria parasite by targeting its housekeeping functions. However, a significant structural difference between bacterial and apicoplast housekeeping proteins promotes the discovery of antibiotic analogs specifically targeting apicoplast proteins. In this study, we used a high-throughput virtual screening approach to analyze 80% of structurally similar antibiotic analog libraries against five protein targets, including histone-like protein (PfHU), gyrase A subunit (PfGyrA), RNA polymerase β subunit (PfRpoβ), elongation factor G (PfEF-G), and elongation factor Tu (PfEF-Tu) involved in different housekeeping functions of the apicoplast. This computational screening identified molecules with better binding affinities than those antibiotics shown to have antimalarial activities, suggesting they may be more potent antimalarial compounds. The molecular dynamics simulations study revealed stable conformational changes with strong hydrogen bonds between the protein–ligand complexes. The top-hit antibiotic analogs exhibit favourable drug-like characteristics, making them promising candidates for future clinical studies. We propose further biochemical and phenotypic testing of these antibiotic analogs to develop more effective apicoplast-targeting antimalarials.