Structure-based Drug Design Studies of the Interactions of Ent-kaurane Diterpenes Derived from Wedelia Paludosa with the Plasmodium Falciparum Sarco/endoplasmic Reticulum Ca²⁺-ATPase PfATP6

Overview

Journal Mem Inst Oswaldo Cruz

Specialties Parasitology
Tropical Medicine

Date 2015 May 7

PMID 25946251

Citations 5

Authors

Daniel Silqueira Martins Guimaraes

Amanda Luisa da Fonseca

Ronan Batista

Moacyr Comar Junior

Alaide Braga de Oliveira

Alex Gutterres Taranto

Fernando de Pilla Varotti

Affiliations

Soon will be listed here.

Abstract

Malaria is responsible for more deaths around the world than any other parasitic disease. Due to the emergence of strains that are resistant to the current chemotherapeutic antimalarial arsenal, the search for new antimalarial drugs remains urgent though hampered by a lack of knowledge regarding the molecular mechanisms of artemisinin resistance. Semisynthetic compounds derived from diterpenes from the medicinal plant Wedelia paludosa were tested in silico against the Plasmodium falciparum Ca2+-ATPase, PfATP6. This protein was constructed by comparative modelling using the three-dimensional structure of a homologous protein, 1IWO, as a scaffold. Compound 21 showed the best docking scores, indicating a better interaction with PfATP6 than that of thapsigargin, the natural inhibitor. Inhibition of PfATP6 by diterpene compounds could promote a change in calcium homeostasis, leading to parasite death. These data suggest PfATP6 as a potential target for the antimalarial ent-kaurane diterpenes.

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References

Krishna S, Pulcini S, Moore C, Teo B, Staines H . Pumped up: reflections on PfATP6 as the target for artemisinins. Trends Pharmacol Sci. 2013; 35(1):4-11. DOI: 10.1016/j.tips.2013.10.007. View

Furuyama W, Enomoto M, Mossaad E, Kawai S, Mikoshiba K, Kawazu S . An interplay between 2 signaling pathways: melatonin-cAMP and IP3-Ca2+ signaling pathways control intraerythrocytic development of the malaria parasite Plasmodium falciparum. Biochem Biophys Res Commun. 2014; 446(1):125-31. DOI: 10.1016/j.bbrc.2014.02.070. View

Meslin B, Beavogui A, Fasel N, Picot S . Plasmodium falciparum metacaspase PfMCA-1 triggers a z-VAD-fmk inhibitable protease to promote cell death. PLoS One. 2011; 6(8):e23867. PMC: 3157471. DOI: 10.1371/journal.pone.0023867. View

Miller L, Ackerman H, Su X, Wellems T . Malaria biology and disease pathogenesis: insights for new treatments. Nat Med. 2013; 19(2):156-67. PMC: 4783790. DOI: 10.1038/nm.3073. View

Krishna S, Pulcini S, Fatih F, Staines H . Artemisinins and the biological basis for the PfATP6/SERCA hypothesis. Trends Parasitol. 2010; 26(11):517-23. DOI: 10.1016/j.pt.2010.06.014. View

Batista R, Garcia P, Castro M, Miguel Del Corral J, Speziali N, de P Varotti F . Synthesis, cytotoxicity and antiplasmodial activity of novel ent-kaurane derivatives. Eur J Med Chem. 2013; 62:168-76. DOI: 10.1016/j.ejmech.2012.12.010. View

Toyoshima C, Nomura H . Structural changes in the calcium pump accompanying the dissociation of calcium. Nature. 2002; 418(6898):605-11. DOI: 10.1038/nature00944. View

Bordoli L, Kiefer F, Arnold K, Benkert P, Battey J, Schwede T . Protein structure homology modeling using SWISS-MODEL workspace. Nat Protoc. 2009; 4(1):1-13. DOI: 10.1038/nprot.2008.197. View

Valderramos S, Scanfeld D, Uhlemann A, Fidock D, Krishna S . Investigations into the role of the Plasmodium falciparum SERCA (PfATP6) L263E mutation in artemisinin action and resistance. Antimicrob Agents Chemother. 2010; 54(9):3842-52. PMC: 2935017. DOI: 10.1128/AAC.00121-10. View

10.

Berman H, Kleywegt G, Nakamura H, Markley J . The future of the Protein Data Bank. Biopolymers. 2012; 99(3):218-22. PMC: 3684242. DOI: 10.1002/bip.22132. View

11.

Gardner M, Hall N, Fung E, White O, Berriman M, Hyman R . Genome sequence of the human malaria parasite Plasmodium falciparum. Nature. 2002; 419(6906):498-511. PMC: 3836256. DOI: 10.1038/nature01097. View

12.

Bagnaresi P, Nakabashi M, Thomas A, Reiter R, Garcia C . The role of melatonin in parasite biology. Mol Biochem Parasitol. 2011; 181(1):1-6. DOI: 10.1016/j.molbiopara.2011.09.010. View

13.

Medebielle M . The medicinal chemistry and drug development of novel antimalarials. Curr Top Med Chem. 2014; 14(14):1635-6. DOI: 10.2174/1568026614666140808152357. View

14.

Bikadi Z, Hazai E . Application of the PM6 semi-empirical method to modeling proteins enhances docking accuracy of AutoDock. J Cheminform. 2010; 1:15. PMC: 2820493. DOI: 10.1186/1758-2946-1-15. View

15.

Lee M, Duan Y . Distinguish protein decoys by using a scoring function based on a new AMBER force field, short molecular dynamics simulations, and the generalized born solvent model. Proteins. 2004; 55(3):620-34. DOI: 10.1002/prot.10470. View

16.

Stewart J . Optimization of parameters for semiempirical methods V: modification of NDDO approximations and application to 70 elements. J Mol Model. 2007; 13(12):1173-213. PMC: 2039871. DOI: 10.1007/s00894-007-0233-4. View

17.

Trott O, Olson A . AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2009; 31(2):455-61. PMC: 3041641. DOI: 10.1002/jcc.21334. View

18.

Nunes-Alves C . Parasite physiology: Propelling artemisinin resistance. Nat Rev Microbiol. 2015; 13(2):66-7. DOI: 10.1038/nrmicro3423. View

19.

Naik P, Srivastava M, Bajaj P, Jain S, Dubey A, Ranjan P . The binding modes and binding affinities of artemisinin derivatives with Plasmodium falciparum Ca2+-ATPase (PfATP6). J Mol Model. 2010; 17(2):333-57. DOI: 10.1007/s00894-010-0726-4. View

20.

Cui L, Wang Z, Jiang H, Parker D, Wang H, Su X . Lack of association of the S769N mutation in Plasmodium falciparum SERCA (PfATP6) with resistance to artemisinins. Antimicrob Agents Chemother. 2012; 56(5):2546-52. PMC: 3346631. DOI: 10.1128/AAC.05943-11. View