INSIGHT INTO THE MOLECULAR INTERACTION OF ANTI MALARIAL COMPOUNDS AS POTENTIAL CHORISMATE SYNTHASE INHIBITORS
Objective: The study is focused and directed towards a promising gateway for novel inhibitor designing against malaria.
Methods: Homology model was built for both ON-state and OFF-state of Plasmodium falciparum chorismate synthase (PfCS) protein. Around 240
antimalarial compounds were docked into the active site of PfCS to understand the interaction and binding affinity. Virtual screening was carried out
based on docking score, molecular properties, drug likeliness and bioactivity toward lead molecule selection.
Results: Based on these properties out of 240 compounds, we found the best fit ligand idarubicin interacting with Arg46, Lys60, Glu86, Arg483 and Arg491
of ON state PfCS, with a high docking score of -13.7. The stability of complex and hydrogen bonds were analysed with molecular dynamic simulations. In
OFF state also idarubicin interacting with a docking score of -15.2 and interacting residues was found to be Ser16, Glu86, Gly126, Arg127 and Arg491.
Conclusion: Malaria, a cataclysmic disease caused by protozoan parasite P. falciparum is a leading disease and cause of death in many of the developing
countries. CS is an enzyme, which plays a major role in the aromatic amino acid biosynthesis of the shikimate pathway. Inhibition of PfCS protein is reported
to affect the growth and survival of the parasite. In this study, idarubicin compound shows anti-parasitic activity and high binding affinity towards PfCS.
Keywords: Homology model, Drug likeliness, Shikimate pathway, Idarubicin.
1. Jana S, Paliwal J. Novel molecular targets for antimalarial chemotherapy. Int J Antimicrob Agents 2007;30(1):4-10.
2. Ludin P, Woodcroft B, Ralph SA, MÃ¤ser P. In silico prediction of antimalarial drug target candidates. Int J Parasitol Drugs Drug Resist 2012;2:191-9.
3. Fidock DA, Rosenthal PJ, Croft SL, Brun R, Nwaka S. Antimalarial drug discovery: efficacy models for compound screening. Nat Rev Drug Discov 2004;3(6):509-20.
4. Arcuri HA, Palma MS. Understanding the structure, activity and inhibition of chorismate synthase from Mycobacterium tuberculosis. Curr Med Chem 2011;18(9):1311-7.
5. Tapas S, Kumar A, Dhindwal S, Preeti, Kumar P. Structural analysis of chorismate synthase from Plasmodium falciparum: a novel target for antimalaria drug discovery. Int J Biol Macromol 2011;49:767-77.
6. Lindner J, Meissner KA, Schettert I, Wrenger C. Trafficked proteins-druggable in Plasmodium falciparum? Int J Cell Biol 2013;2013:435981.
7. Viola CM, Saridakis V, Christendat D. Crystal structure of chorismate synthase from Aquifex aeolicus reveals a novel beta alpha beta sandwich topology. Proteins 2004;54(1):166-9.
8. Arora N, Chari UM, Banerjee AK, Murty U. A computational approach to explore Plasmodium falciparum 3D7 chorismate synthase. Int J Genomics Proteomics 2007;3(1):3-28.
9. Quevillon-Cheruel S, Leulliot N, Meyer P, Graille M, Bremang M, Blondeau K, et al. Crystal structure of the bifunctional chorismate synthase from Saccharomyces cerevisiae. J Biol Chem 2004;279(1):619-25.
10. Ahn HJ, Yoon HJ, Lee B nd, Suh SW. Crystal structure of chorismate synthase: a novel FMN-binding protein fold and functional insights. J Mol Biol 2004;336(4):903-15.
11. Fitzpatrick T, Ricken S, Lanzer M, Amrhein N, Macheroux P, Kappes B. Subcellular localization and characterization of chorismate synthase in the apicomplexan Plasmodium falciparum. Mol Microbiol 2001;40(1):65-75.
12. Thompson JD, Higgins DG, Gibson TJ. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 1994;22(22):4673-80.
13. Sali A, Blundell TL. Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 1993;234(3):779-815.
14. Laskowski RA, MacArthur MW, Moss DS, Thornton JM. PROCHECK: A program to check the stereochemical quality of protein structures. J Appl Crystallogr 1993;26:283-91.
15. Wiederstein M, Sippl MJ. ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Res 2007;35(Web Server issue):W407-10.
16. Hess B, Kutzner C, Van der Spoel D, Lindahl E. GROMACS 4: Algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theory Comput 2008;4:435-47.
17. Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010;31(2):455-61.
18. DeLano WL. The PyMOL Molecular Graphics System. San Carlos, CA: DeLano Scientific LLC; 2002.
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