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.
drug resistance and control in Indonesia. Adv Parasitol 2011;74:
2. JordÃ£o FM, Gabriel HB, Alves JM, Angeli CB, Bifano TD, Breda A,
et al. Cloning and characterization of bifunctional enzyme farnesyl
diphosphate/geranylgeranyl diphosphate synthase from Plasmodium
falciparum. Malar J 2013;12:184.
3. Artz JD, Wernimont AK, Dunford JE, Schapira M, Dong A,
Zhao Y, et al. Molecular characterization of a novel geranylgeranyl
pyrophosphate synthase from Plasmodium parasites. J Biol Chem
4. Crowther GJ, Napuli AJ, Gilligan JH, Gagaring K, Borboa R,
Francek C, et al. Identification of inhibitors for putative malaria drug
targets among novel antimalarial compounds. Mol Biochem Parasitol
5. Pholphana N, Rangkadilok N, Saehun J, Ritruechai S, Satayavivad J.
Changes in the contents of four active diterpenoids at different growth
stages in Andrographis paniculata (Burm.f.) Nees (Chuanxinlian).
Chin Med 2013;8(2):1-12.
6. Mishra K, Dash AP, Dey N. Andrographolide: A novel antimalarial
diterpene lactone compound from Andrographis paniculata
and its interaction with curcumin and artesunate. J Trop Med
7. Srivastava N, Akhila A. Biosynthesis of andrographolide in
Andrographis paniculata. Phytochemistry 2010;71(11-12):1298-304.
Supplementary Fig. 3: Left: Docking pose of 1 (light blue sticks), 2a (purple sticks), and 2b (yellow sticks), in Plasmodium falciparum
geranylgeranyl pyrophosphate synthase model; aspartates in first aspartate-rich motif and second aspartate-rich motif depicted in
blue wires and labeled; image captured using PyMOL Molecular Graphics System (at http://www.pymol.org/) . Right: Structures of
andrographolide (1), 2a, and 2b
Int J App Pharm, Special Issue (October)
Putra et al.
8. Larkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA,
McWilliam H, et al. Clustal W and Clustal X version 2.0. Bioinformatics
9. Kuntal BK, Aparoy P, Reddanna P. EasyModeller: A graphical interface
to MODELLER. BMC Res Notes 2010;3:226.
10. Oâ€™Boyle NM, Banck M, James CA, Morley C, Vandermeersch T,
Hutchison GR. Open Babel: An open chemical toolbox. J Cheminform
11. Ye L, Wang T, Tang L, Liu W, Yang Z, Zhou J, et al. Poor oral
bioavailability of a promising anticancer agent andrographolide is due
to extensive metabolism and efflux by P-glycoprotein. J Pharm Sci
12. DeLano WL. The PyMOL Molecular Graphics System. Palo Alto, CA:
DeLano Scientific; 2008.