Advertisement

Parthenin and Its Similar Structure as Potential Lead Inhibitors of Plasmodium vivax and Plasmodium falciparum Lactate Dehydrogenase

  • Pushpendra Singh
  • Prem P. Kushwaha
  • Shashank Kumar
Chapter

Abstract

Blood-borne parasite, Plasmodium vivax and Plasmodium falciparum are the most severe malaria causing organisms. Drug resistance against the present antimalarial drugs increased malaria-related morbidity and mortality. Inter-conversion of lactate and pyruvate in the glycolytic pathway requires a metabolic enzyme called lactate dehydrogenase A (LDHA). In recent years, anti-malarial therapy included several small molecules which are LDHA inhibitor in nature. Parthenin is the most active phytochemical of Parthenium hysteropohorus (Asteraceae). Maestro 9.6 software package was used for docking of parthenin like compounds (n = 85) against P. vivax, P. falciparum and the Homo sapiens lactate dehydrogenase proteins (PDB 2A92, 2A94, and 4R68 respectively) to appraise the interaction pattern of target protein and selected ligands. Docking analysis explored some ligands having excellent binding affinity against P. vivax (CID72786361, 78178433, and 11552273), P. falciparum (CID296217, 3482907, 77977597, 78178433). These lead compounds does not showed interaction with the mammalian LDH protein. Glide docking score of selected compounds and standard inhibitor of the target proteins ranged from −5.58 to −8.6 to −6.8 to −7.38 respectively. Structural investigation of selected ligands with P. vivax, P. falciparum, and mammalian LDH complexes revealed the involvement of strong hydrophobic interactions and hydrogen bonding pattern. The QikProp module of Maestro 9.6 was used to predict ADME/T (Absorption, Distribution, Metabolism, Excretion and Toxicity) properties of the lead compounds. In conclusion, CID72786361, 78178433, 11552273 and CID296217, 3482907, 77977597, 78178433 may serve as lead LDHA inhibitor compounds to target P. vivax and P. falciparum malarial parasite respectively. Further in vitro and in vivo studies are required to assess the anti-malarial drug discovery potential of the parthenin like compounds.

Keywords

Lactate dehydrogenase A (LDHA) Malaria Parthenin like compounds Maestro 9.6 

Notes

Acknowledgments

PS and PPK acknowledge Indian Council of Medical Research (ICMR), India and UGC-CSIR, India respectively for providing the financial assistance in the form of Postdoc and Senior Research Fellowship. SK acknowledges the Central University of Punjab for providing infrastructure facilities.

References

  1. Becker S, Groner B, Müller CW. Three-dimensional structure of the Stat3β homodimer bound to DNA. Nature. 1998;394(6689):145–51.CrossRefGoogle Scholar
  2. Chaikuad A, Fairweather V, Conners R, Joseph-Horne T, Turgut-Balik D, Leo R. Brady structure of lactate dehydrogenase from Plasmodium Vivax: complexes with NADH and APADH†. Biochemistry. 2005;44:16221–8.CrossRefGoogle Scholar
  3. Chen C. Development of antimalarial drugs and their application in China: a historical review. Infect Dis Poverty. 2014;3(1):1–10.CrossRefGoogle Scholar
  4. Ekins S, Mestres J, Testa B. In silico pharmacology for drug discovery: applications to targets and beyond. Br J Pharmacol. 2007;152(1):21–37.CrossRefGoogle Scholar
  5. Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, Shaw DE. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem. 2004;47(7):1739–49.CrossRefGoogle Scholar
  6. Jorgensen WL, Duffy EM. Prediction of drug solubility from structure. Adv Drug Deliv Rev. 2002;54(3):355–66.CrossRefGoogle Scholar
  7. Jorgensen WL, Tirado-Rives J. The OPLS [optimized potentials for liquid simulations] potential functions for proteins, energy minimizations for crystals of cyclic peptides and crambin. J Am Chem Soc. 1988;110(6):1657–66.CrossRefGoogle Scholar
  8. Jorgensen WL, Maxwell DS, Tirado-Rives J. Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J Am Chem Soc. 1996;118(45):11225–36.CrossRefGoogle Scholar
  9. Kerns E, Di L. Drug-like properties: concepts, structure design and methods: from ADME to toxicity optimization. Amsterdam: Academic Press; 2010.Google Scholar
  10. Kongsaeree P, Khongsuk P, Leartsakulpanich U, Chitnumsub P, Tarnchompoo B, Walkinshaw MD, Yuthavong Y. Crystal structure of dihydrofolate reductase from Plasmodium vivax: pyrimethamine displacement linked with mutation-induced resistance. Proc Natl Acad Sci U S A. 2005;102(37):13046–51.CrossRefGoogle Scholar
  11. Kumar S, Mishra A, Pandey AK. Antioxidant mediated protective effect of Parthenium hysterophorus against oxidative damage using in vitro models. BMC Complement Altern Med. 2013;120:1–9.Google Scholar
  12. Labadie S, Dragovich PS, Chen J, Fauber BP, Boggs J, Corson LB. Optimization of 5-(2, 6-dichlorophenyl)-3-hydroxy-2-mercaptocyclohex-2-enones as potent inhibitors of human lactate dehydrogenase. Bioorg Med Chem Lett. 2015;25(1):75–82.CrossRefGoogle Scholar
  13. Lu JJ, Crimin K, Goodwin JT, Crivori P, Orrenius C, Xing L, Tandler PJ, Vidmar TJ, Amore BM, Wilson AG, Stouten PF. Influence of molecular flexibility and polar surface area metrics on oral bioavailability in the rat. J Med Chem. 2004;47(24):6104–7.CrossRefGoogle Scholar
  14. Qidwai T, Jamal F, Khan MY, Sharma B. Exploring drug targets in isoprenoid biosynthetic pathway for Plasmodium falciparum. Biochem Res Int. 2014;2014:1–12.CrossRefGoogle Scholar
  15. Ramya TNC, Surolia N, Surolia A. Survival strategies of the malarial parasite Plasmodium falciparum. Curr Sci. 2002;83(7):818–25.Google Scholar
  16. Shivakumar D, Williams J, Wu Y, Damm W, Shelley J, Sherman W. Prediction of absolute solvation free energies using molecular dynamics free energy perturbation and the OPLS force field. J Chem Theory Comput. 2010;6(5):1509–19.CrossRefGoogle Scholar
  17. Singh P, Kushwaha PP, Kumar S. Novel potent inhibitors of Plasmodium vivax dihydrofolate reductase: an in silico antimalarial drug discovery. Indian J Pharm Educ Res. 2018;52:1–14.CrossRefGoogle Scholar
  18. Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem. 2002;45(12):2615–23.CrossRefGoogle Scholar
  19. WHO. World malaria report 2011. Geneva: World Health Organ; 2011.Google Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Pushpendra Singh
    • 1
  • Prem P. Kushwaha
    • 2
  • Shashank Kumar
    • 2
  1. 1.Tumor Biology LaboratoryNational Institute of PathologyNew DelhiIndia
  2. 2.Department of Biochemistry and Microbial SciencesCentral University of PunjabBathindaIndia

Personalised recommendations