Predicted binding mode of andrographolide and its derivatives bound to Plasmodium falciparum geranylgeranyl pyrophosphate synthase

Objective: Andrographolide is a major secondary metabolite in the Indonesian herb sambiloto (Andrographis paniculata). It displays a moderate antiplasmodial activity against the chloroquine-resistant strain of Plasmodium falciparum. This study aimed to investigate andrographolide inhibition of geranylgeranyl pyrophosphate synthase (GGPPS) by andrographolide molecular docking. Methods: A comparative modeling of P. falciparum GGPPS was conducted using one of the Plasmodium vivax GGPPS crystal structures as a template. The best model from this comparative modeling was then used in a molecular docking to investigate the binding mode of andrographolide in the P. falciparum GGPPS active site. Results: In the P. falciparum GGPPS active site, andrographolide is situated with its double rings pointing toward the hydrophobic pocket, while its lactone group is positioned between first aspartate-rich motif and second aspartate-rich motif of the catalytic pocket. Conclusions: In the active site, andrographolide is situated with its double rings pointing toward the hydrophobic pocket, while its lactone group is positioned in the catalytic pocket.