In silico Studies on Selected Drug Targets for Combating Drug Resistance in Plasmodium falcifarum
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.
[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
[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
@article{"International Journal of Medical, Medicine and Health Sciences:69394", author = "D. Bhaskar and N. R. Wadehra and M. Gulati and A. Narula and R. Vishnu and G. Katyal", title = "In silico Studies on Selected Drug Targets for Combating Drug Resistance in Plasmodium falcifarum", 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.", volume = "9", number = "2", pages = "188-5", }
