Molecular modelling based target identification for endo-peroxides class of antimalarials

Area of Science:

• Medicinal Chemistry
• Parasitology
• Drug Discovery

Background:

• Artemisinin and endoperoxide drug resistance is a growing threat to malaria control.
• The precise mechanism of action for these antimalarials remains elusive, hindering resistance management and new drug development.

Purpose of the Study:

• To investigate the molecular targets of artemisinin derivatives using computational methods.
• To differentiate between heme and PfATP6 as potential targets for artemisinin-derived endoperoxides.

Main Methods:

• Molecular docking and scoring studies were conducted on a diverse dataset of artemisinin derivatives.
• A homology model for Plasmodium falciparum ATP6 (PfATP6) was constructed using human SERCA1 as a template.

Main Results:

• Docking studies showed a strong correlation between binding energy at the heme site and antimalarial activity (r² = 0.69).
• Conversely, a weak correlation was observed between binding energy at the PfATP6 site and antimalarial activity (r² = 0.12).

Conclusions:

• These findings strongly suggest that heme is the primary molecular target of artemisinin-derived endoperoxides.
• Identifying heme as the target provides crucial insights for understanding drug resistance and designing next-generation antimalarials.