Objective: Andrographolide was found to show moderate antimalarial activity against chloroquine-resistant strain of Plasmodium falciparum (PF). It thus becomes an interesting lead for new antimalarial drugs. This study describes a molecular docking of andrographolide and its derivative into the best PF geranylgeranyl pyrophosphate synthase (PFGGPPS) model. Methods: A comparative modeling of PFGGPPS based on a crystal structure of Plasmodium vivax GGPPS was optimized and conducted. This model was considered suitable for molecular docking. Partition coefficient of andrographolide was determined to assist its derivative design based on hydrophobicity property. Synthesis of the antimalarial drug was scaled up to 5 mm and identified by13 C- and1H-nuclear magnetic resonance (NMR) spectroscopy. Results: The optimal comparative modeling of PFGGPPS was conducted on chain B (3PH7 chain B). The calculated coefficient partition of andrographolide’s derivative was higher (+1.89), compared to that of andrographolide of +1.62. The NMR data of second and third synthesis experiments were consistent at the 5-mmol scale. Conclusions: On the molecular docking of andrographolide into the model, an antimalarial andrographolide derivative design that is more hydrophobic than andrographolide was proposed since the stronger hydrophobicity property of drug, the better of its activity of the drug. Synthesis of this derivative with a simple and green procedure was found to be reproducible.
- Comparative modeling
- Drug design and synthesis
- Geranylgeranyl pyrophosphate synthase
- Molecular docking
- Plasmodium falciparum