Source Code Biol Med. 2015 May 22;10:7. doi: 10.1186/s13029-015-0037-3. eCollection 2015.
Molecular-docking study of malaria drug target enzyme transketolase in Plasmodium falciparum 3D7 portends the novel approach to its treatment.
Source code for biology and medicine
Md Anayet Hasan, Md Habibul Hasan Mazumder, Afrin Sultana Chowdhury, Amit Datta, Md Arif Khan
Affiliations
Affiliations
- Department of Genetic Engineering and Biotechnology, Faculty of Biological Sciences, University of Chittagong, Chittagong, 4331 Bangladesh.
- Department of Biotechnology and Genetic Engineering, Mawlana Bhashani Science and Technology University, Santosh, Tangail, 1902 Bangladesh.
PMID: 26089981
PMCID: PMC4472393 DOI: 10.1186/s13029-015-0037-3
Abstract
BACKGROUND: Malaria has been a major life threatening mosquito borne disease from long since. Unavailability of any effective vaccine and recent emergence of multi drug resistant strains of malaria pathogen Plasmodium falciparum continues to cause persistent deaths in the tropical and sub-tropical region. As a result, demands for new targets for more effective anti-malarial drugs are escalating. Transketolase is an enzyme of the pentose phosphate pathway; a novel pathway which is involved in energy generation and nucleic acid synthesis. Moreover, significant difference in homology between Plasmodium falciparum transketolase (Pftk) and human (Homo sapiens) transketolase makes it a suitable candidate for drug therapy. Our present study is aimed to predict the 3D structure of Plasmodium falciparum transketolase and design an inhibitor against it.
RESULTS: The primary and secondary structural features of the protein is calculated by ProtParam and SOPMA respectively which revealed the protein is composed of 43.3 % alpha helix and 33.04 % random coils along with 15.62 % extended strands, 8.04 % beta turns. The three dimensional structure of the transketolase is constructed using homology modeling tool MODELLAR utilizing several available transketolase structures as templates. The structure is then subjected to deep optimization and validated by structure validation tools PROCHECK, VERIFY 3D, ERRAT, QMEAN. The predicted model scored 0.74 for global model reliability in PROCHECK analysis, which ensures the quality of the model. According to VERIFY 3D the predicted model scored 0.77 which determines good environmental profile along with ERRAT score of 78.313 which is below 95 % rejection limit. Protein-protein and residue-residue interaction networks are generated by STRING and RING server respectively. CASTp server was used to analyze active sites and His 109, Asn 108 and His 515 are found to be more positive site to dock the substrate, in addition molecular docking simulation with Autodock vina determined the estimated free energy of molecular binding was of -6.6 kcal/mol for most favorable binding of 6'-Methyl-Thiamin Diphosphate.
CONCLUSION: This predicted structure of Pftk will serve first hand in the future development of effective Pftk inhibitors with potential anti-malarial activity. However, this is a preliminary study of designing an inhibitor against Plasmodium falciparum 3D7; the results await justification by in vitro and in vivo experimentations.
Keywords: Docking studies; Drug target; Homology modeling; Plasmodium falciparum 3D7; Transketolase
References
- Protein Sci. 1998 Sep;7(9):1884-97 - PubMed
- BMC Struct Biol. 2009 May 20;9:35 - PubMed
- J Biochem. 1980 Dec;88(6):1895-8 - PubMed
- Nat Protoc. 2007;2(10):2366-82 - PubMed
- Nature. 2002 Feb 7;415(6872):670-2 - PubMed
- Curr Med Chem. 2008;15(2):161-71 - PubMed
- J Theor Biol. 2014 Dec 7;362:44-52 - PubMed
- PLoS Comput Biol. 2010 Nov 04;6(11):e1000978 - PubMed
- J Mol Biol. 1999 Oct 22;293(2):321-31 - PubMed
- Biophys J. 2011 Nov 16;101(10):2525-34 - PubMed
- Bioinformatics. 1999 May;15(5):413-21 - PubMed
- Proteins. 2008 Apr;71(1):261-77 - PubMed
- Nat Med. 2013 Feb;19(2):156-67 - PubMed
- Genome Res. 2003 Nov;13(11):2498-504 - PubMed
- Int J Antimicrob Agents. 2007 Jul;30(1):4-10 - PubMed
- Mol Immunol. 2015 May;65(1):189-204 - PubMed
- Curr Drug Targets. 2009 Mar;10(3):271-8 - PubMed
- J Mol Graph Model. 2001;19(1):26-59 - PubMed
- Genomics Inform. 2014 Dec;12(4):268-75 - PubMed
- Nature. 2002 Feb 7;415(6872):673-9 - PubMed
- Genome Biol. 2007;8(5):R92 - PubMed
- Proc Natl Acad Sci U S A. 2009 Sep 1;106(35):14902-7 - PubMed
- Protein Sci. 1993 Sep;2(9):1511-9 - PubMed
- Lancet. 2012 Feb 4;379(9814):413-31 - PubMed
- Folia Biol (Praha). 2000;46(6):210-8 - PubMed
- EMBO J. 1986 Apr;5(4):823-6 - PubMed
- Nucleic Acids Res. 2001 Jul 15;29(14):2994-3005 - PubMed
- FEBS Lett. 2011 Jun 6;585(11):1551-62 - PubMed
- Methods Enzymol. 1997;277:396-404 - PubMed
- Nature. 2002 Oct 3;419(6906):498-511 - PubMed
- Mol Biochem Parasitol. 2011 Jan;175(1):21-9 - PubMed
- Nucleic Acids Res. 2000 Sep 15;28(18):3442-4 - PubMed
- Malar J. 2005 Mar 18;4:17 - PubMed
- Anal Biochem. 1989 Nov 1;182(2):319-26 - PubMed
- Protein Sci. 2002 Apr;11(4):739-56 - PubMed
- J Biomol Struct Dyn. 2015;33(11):2421-41 - PubMed
- J Mol Biol. 1963 Jul;7:95-9 - PubMed
- J Comput Chem. 2010 Jan 30;31(2):455-61 - PubMed
- J Bacteriol. 1992 Nov;174(22):7337-44 - PubMed
- PLoS One. 2010 Feb 23;5(2):e9391 - PubMed
- Nucleic Acids Res. 2009 Jan;37(Database issue):D657-60 - PubMed
- J Clin Invest. 2010 Dec;120(12):4168-78 - PubMed
- Mol Biochem Parasitol. 2008 Jul;160(1):32-41 - PubMed
- Trends Biochem Sci. 2011 Apr;36(4):179-82 - PubMed
- Science. 1991 Jul 12;253(5016):164-70 - PubMed
- Methods Enzymol. 2006;411:408-21 - PubMed
- Nucleic Acids Res. 2003 Jul 1;31(13):3701-8 - PubMed
- J Biomol NMR. 1996 Dec;8(4):477-86 - PubMed
- Electrophoresis. 1997 Dec;18(15):2714-23 - PubMed
- Toxicol Int. 2014 Sep-Dec;21(3):269-74 - PubMed
- J Biomol NMR. 2014 Apr;58(4):259-85 - PubMed
- Nucleic Acids Res. 2013 Jan;41(Database issue):D808-15 - PubMed
- Nucleic Acids Res. 2007 Jan;35(Database issue):D590-4 - PubMed
- Drug Target Insights. 2014 Jan 13;8:1-9 - PubMed
- Protein Eng. 1990 Dec;4(2):155-61 - PubMed
- Bioinformatics. 2011 Feb 1;27(3):343-50 - PubMed
- Biochem J. 2011 Jun 15;436(3):641-50 - PubMed
- Bioinformatics. 2011 Jul 15;27(14):2003-5 - PubMed
- Proc Natl Acad Sci U S A. 2012 Aug 7;109(32):13052-7 - PubMed
- Comput Appl Biosci. 1995 Dec;11(6):681-4 - PubMed
- Lancet Infect Dis. 2010 Aug;10(8):545-55 - PubMed
- Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W116-8 - PubMed
- Nucleic Acids Res. 2009 Jul;37(Web Server issue):W510-4 - PubMed
- J Mol Biol. 1993 Dec 5;234(3):779-815 - PubMed
- Traffic. 2015 May;16(5):461-75 - PubMed
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