Computational Investigation of Lupeol Acetylsalicylate Derivatives as Potential Antimalarial Agents Targeting Plasmodium falciparum Hsp 90 and SERA 6 Proteins

Abstract

Plasmodium falciparum, the most virulent malaria parasite, is evolving resistance to current drugs, necessitating new therapeutics. The aim of this study is to investigate lupeol acetylsalicylate derivatives as potential antimalarial agents targeting Plasmodium falciparum Hsp90 (which stabilises proteins that are inherently unstable, many of which are critical for signal transduction and cellular regulation) and SERA6 protein which contributes to the last stages of RBC rupture, which allows new parasites (merozoites) to be released and infect more RBCs. This study employs in silico docking to identify potential inhibitors for two key targets i.e. Heat Shock 90 kDa Protein (Hsp 90) and SERA 6. Several optimized compounds (Opt), including Opt 94, Opt 140, Opt 66, Opt 88, Opt 58, and Opt 100 were evaluated for their binding affinity, stability, and interaction profiles. Among these, Opt 94 demonstrated the strongest binding affinity, with a docking score of -4.059 kcal/mol and a favourable MMGBSA dG Bind value of -60.24 kcal/mol, indicating a stable interaction with Hsp 90. In comparison, Artemether (standard inhibitor) exhibited weaker binding interactions, further emphasizing the potential of Opt 94. Furthermore, Opt 88 emerged as another promising candidate, with the most favourable MMGBSA dG Binding value of -62.88 kCal/mol against SERA 6, suggesting optimal binding stability. These findings highlight Opt 94 and Opt 88 as promising candidates for further development as P. falciparum inhibitors, offering a potential new direction in the fight against malaria.