In silico Studies on Selected Drug Targets for Combating Drug Resistance in Plasmodium falcifarum

Authors: D. Bhaskar, N. R. Wadehra, M. Gulati, A. Narula, R. Vishnu, G. Katyal

Abstract:

With drug resistance becoming widespread in Plasmodium falciparum infections, the development of the alternative drugs is the desired strategy for prevention and cure of malaria. Three drug targets were selected to screen promising drug molecules from the GSK library of 13469 molecules. Using an in silico structure-based drug designing approach, the differences in binding energies of the substrate and inhibitor were exploited between target sites of parasite and human to design a drug molecule against Plasmodium. The docking studies have shown several promising molecules from GSK library with more effective binding as compared to the already known inhibitors for the drug targets. Though stronger interaction has been shown by several molecules as compared to the reference, few molecules have shown the potential as drug candidates though in vitro studies are required to validate the results. In case of thymidylate synthase-dihydrofolatereductase (TS-DHFR), three compounds have shown promise for future studies as potential drugs.

Keywords: Drug resistance, Drug targets, In silico studies, Plasmodium falciparum.

Digital Object Identifier (DOI): doi.org/10.5281/zenodo.1099964

References:

[1] World Malaria Report 2012 Fact Sheet, http://www.who.int/ malaria/publications/world_malaria_report_2012/en/index.html
[2] Marco A. Biamonte, Jutta Wanner, Karine G. Le Roch, 2013, Recent advances in malaria drug discovery Bioorganic & Medicinal Chemistry Letters 23 (2013) 2829–2843.
[3] D. Sinclair, B. Zani, S Donegan, P Olliaro, P Garner, Artemisinin-based combination therapy for treating uncomplicated malaria, The Cochrane Library 2009, Issue 4.
[4] Piero L. Olliaro and Walter R. J. Taylor, 2003, Antimalarial compounds: from bench to bedside The Journal of Experimental Biology 206, 3753- 3759
[5] P T Mpangase, M J Szolkiewicz, M le Grange, J H Smit, P B Burger and F Joubert Discovery-2: an interactive resource for the rational selection and comparison of putative drug target proteins in malaria Malaria Journal 2013,12:116 http://www.malariajournal.com/content/12/1/11
[6] B. T. Grimbergand R. K. Mehlotra Expanding the Antimalarial Drug Arsenal—Now, But How? Pharmaceuticals (Basel). 2011 May 1; 4(5): 681–712. doi:10.3390/ph4050681.
[7] T Dasgupta Exploiting Structural Analysis, In silico Screening and Serendipity to Identify Novel Inhibitors of Drug-resistant Falciparum Malaria ACS Chem Biol. 2009 January 16; 4(1): 29–40. doi:10.1021/cb8002804.
[8] P. Sivaprakasam, P. N. Tosso, and R. J. Doerksen Structure-activity relationship and comparative docking studies for cycloguanil analogs as PfDHFR-TS inhibitors JChemInf Model. 2009 July; 49(7): 1787–1796. doi:10.1021/ci9000663.
[9] J. Yuvanijyama., P. Chitnumsub et al, Insights into antifolate resistance from malarial DHFR-TS structures, Nature Struct. Biol, Vol. 10, pp 357- 365 2003. Doi: 10.1038/nsb921
[10] T. Dasgupta., P. Chitnumsub et al, Exploiting structural analysis, in silico screening and serendipity to identify novel inhibitors of drugresistant falciparum malaria, ACS Chemical Biol. , Vol. 16:4(1): 29-40 doi: 10.1021/cb8002804
[11] N. Sawada., N. Nagahara et al The activation mechanism of human porphobilinogen synthase by 2-mercaptoethanol: intrasubunit transfer of a reserve zinc ion and coordination with three cysteines in the active center, J. BiolInorg Chem, Vol 10 (2):199-207. Epub 2005 Mar 4.
[12] Y.F. Long., Q.G. Liao., C.Z. Huang and Y.F. Li, Conformational change detection of DNA with the fluorogenic reagent of o-phthalaldehydebeta- mercaptoethanol, J. Phys Chem, Vol 112(6): 1783-8, doi: 10.1021/jp071601g. Epub 2008 Jan 24
[13] Inhibitors extracted from pdb database http://www.rcsb.org/pdb/ligand/ligandsummary
[14] A. Spitzmuller, J. MestresPrediction of the P. falciparum Target Space Relevant to Malaria Drug Discovery, PLoSComputBiol2013 Vol. 9(10): 003257.doi:10.1371/journal.pcbi.1003257
[15] N. A. Bispo, R. Culleton, L. Almeida Silva, P. Cravo, A Systematic In Silicosearch for target similarity identifies several approved drugs with potential activity against the Plasmodium falciparum apicoplast, .PLoS ONE March 26, 2013 Vol. 8(3): e59288. doi:10.1371/journal.pone.0059288.
[16] A Krammer, P. D. Kirchhoff1, X. Jiang, C.M. Venkatachalam, M. Waldman LigScore: a novel scoring function for predicting binding Affinities Accelrys Inc., 10188 Telesis Court, Suite 100, San Diego, CA 92121, USA Available online 25 December 2004