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An in silico strategy for identification of novel drug targets against Plasmodium falciparum

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Abstract

The apicomplexan parasite Plasmodium falciparum is responsible for global malaria burden. With the reported resistance to artemisinin chemotherapy, there is an urgent need to maintain early phase drug discovery and identify novel drug targets for successful eradication of the pathogen from the host. In our previous work on comparative genomics study for identification of putative essential genes and therapeutic candidates in P. falciparum, we predicted 11 proteins as anti-malarial drug targets from PlasmoDB database. In this paper, we made an attempt for identification of novel drug targets in P. falciparum genome using a sequence of computational methods from Malaria Parasite Metabolic Pathway database. The study reported the identification of 71 proteins as potential drug targets for anti-malarial interventions. Furthermore, homology modeling and molecular dynamic simulation study of one of the potential drug targets, aminodeoxychorismate lyase, was carried to predict the 3D structure of the protein. Structure and ligand-based drug designing reported MMV019742 from Pathogen Box and TCAMS-141515 from GSK-TCAMS library as potential hits. The reliability of the binding mode of the inhibitors is confirmed by GROMACS for a simulation time of 20 ns in water environment. This will be helpful for experimental validation of the small-molecule inhibitor.

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References

  • Ariey F, Witkowski B, Amaratunga C, Beghain J, Langlois AC, Khim N, Lim P (2014) A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature 505:50–55

    Article  PubMed  Google Scholar 

  • Aurrecoechea C, Brestelli J, Brunk BP, Dommer J, Fischer S, Gajria B, Heiges M (2009) PlasmoDB: a functional genomic database for malaria parasites. Nucleic Acids Res 37:D539–D543

    Article  CAS  PubMed  Google Scholar 

  • Barmade MA, Murumkar PR, Kumar Sharma M, Shingala KP, Giridhar RR, Yadav MR (2015) Discovery of anti-malarial agents through application of in silico studies. Comb Chem High Throughput Screen 18:151–187

    Article  CAS  PubMed  Google Scholar 

  • Berendsen HJ, van der Spoel D, van Drunen R (1995) GROMACS: a message-passing parallel molecular dynamics implementation. Comput Phys Commun 91:43–56

    Article  CAS  Google Scholar 

  • Bernstein FC, Koetzle TF, Williams GJ, Meyer EF, Brice MD, Rodgers JR, Tasumi M (1978) The Protein Data Bank: a computer-based archival file for macromolecular structures. Arch Biochem Biophys 185:584–559

    Article  CAS  PubMed  Google Scholar 

  • Bhasin M, Raghava GPS (2004) ESLpred: SVM-based method for subcellular localization of eukaryotic proteins using dipeptide composition and PSI-BLAST. Nucleic Acids Res 32:W414–W419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Camach C, Coulouris G, Avagyan V, Ma N, Papadopoulos J, Bealer K, Madden TL (2009) BLAST+: architecture and applications. BMC Bioinformatics 10(1):421

    Article  Google Scholar 

  • Chang TH, Wu LC, Lee TY, Chen SP, Huang HD, Horng JT (2013) EuLoc: a web-server for accurately predict protein subcellular localization in eukaryotes by incorporating various features of sequence segments into the general form of Chou’s PseAAC. J Comput Aided Mol Des 27(1):91–103

    Article  CAS  PubMed  Google Scholar 

  • Colovos C, Yeates TO (1993) Verification of protein structures: patterns of nonbonded atomic interactions. Protein Sci 2:1511–1519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Conesa A, Götz S, García-Gómez JM, Terol J, Talón M, Robles M (2005) Blast2GO: a universal tool for annotation, visualization and analysis in functional genomics research. Bioinformatics 21:3674–3676

    Article  CAS  PubMed  Google Scholar 

  • Darden T, York D, Pedersen L (1993) Particle mesh Ewald: an n.Log (N) method for Ewald sums in large systems. J Chem Phys 98(12):10089–10092

    Article  CAS  Google Scholar 

  • Eisenberg D, Lüthy R, Bowie JU (1997) VERIFY3D: assessment of protein models with three-dimensional profiles. Methods Enzymol 277:396–404

    Article  CAS  PubMed  Google Scholar 

  • Elliott DA, McIntosh MT, Hosgood HD, Chen S, Zhang G, Baevova P, Joiner KA (2008) Four distinct pathways of hemoglobin uptake in the malaria parasite Plasmodium falciparum. PNAS 105(7):2463–2468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gamo FJ, Sanz LM, Vidal J, de Cozar C, Alvarez E, Lavandera JL, Brown JR (2010) Thousands of chemical starting points for antimalarial lead identification. Nature 465(7296):305–310

    Article  CAS  PubMed  Google Scholar 

  • Geourjon C, Deleage G (1995) SOPMA: significant improvements in protein secondary structure prediction by consensus prediction from multiple alignments. Bioinformatics 11(6):681–684

    Article  CAS  Google Scholar 

  • Ginsburg H (2006) Progress in in silico functional genomics: the malaria metabolic pathways database. Trends Parasitol 22(6):238–240

    Article  CAS  PubMed  Google Scholar 

  • Ginsburg H (2009) Caveat emptor: limitations of the automated reconstruction of metabolic pathways in Plasmodium. Trends Parasitol 25(1):37–43

    Article  CAS  PubMed  Google Scholar 

  • Ginsburg H, Tilley L (2011) Plasmodium falciparum metabolic pathways (MPMP) project upgraded with a database of subcellular locations of gene products. Trends Parasitol 27(7):285–286

    Article  CAS  PubMed  Google Scholar 

  • Hess B, Bekker H, Berendsen HJ, Fraaije JG (1997) LINCS: a linear constraint solver for molecular simulations. J Comput Chem 18(12):1463–1472

    Article  CAS  Google Scholar 

  • Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14(1):33–38

    Article  CAS  PubMed  Google Scholar 

  • Hunter S, Apweiler R, Attwood TK, Bairoch A, Bateman A, Binns D, Finn RD (2009) InterPro: the integrative protein signature database. Nucleic Acids Res 37:D211–D215

    Article  CAS  PubMed  Google Scholar 

  • Hyde JE (2005) Exploring the folate pathway in Plasmodium falciparum. Acta Trop 94(3):191–206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Irwin JJ, Shoichet BK (2005) ZINC—a free database of commercially available compounds for virtual screening. J Chem Inf Model 45(1):177–182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jorgensen WL, Tirado-Rives J (1988) The OPLS [optimized potentials for liquid simulations] potential functons for proteins, energy minimizations for crystals of cyclic peptides and crambin. J Am Chem Soc 110(6):1657–1666

    Article  CAS  PubMed  Google Scholar 

  • Kim S, Thiessen PA, Bolton EE, Chen J, Fu G, Gindulyte A, Han L, He J, He S, Shoemaker BA, Wang J, Yu B, Zhang J, Bryant SH (2016) PubChem substance and compound databases. Nucleic Acids Res 44(D1):D1202–D1213

    Article  CAS  PubMed  Google Scholar 

  • Laskowski RA, MacArthur MW, Moss DS, Thornton JM (1993) PROCHECK: a program to check the stereo chemical quality of protein structures. J App Crystallogr 26(2):283–291

    Article  CAS  Google Scholar 

  • Lemkul JA, Allen WJ, Bevan DR (2010) Practical considerations for building GROMOS-compatible small-molecule topologies. J Chem Informat Mod 50(12):2221–2235

    Article  CAS  Google Scholar 

  • Li L, Stoeckert CJ, Roos DS (2003) OrthoMCL: identification of ortholog groups for eukaryotic genomes. Genome Res 13(9):2178–2189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ludin P, Woodcroft B, Ralph SA, Mäser P (2012) In silico prediction of antimalarial drug target candidates. International Journal for Parasitology: Drugs and Drug Resistance 2:191–199

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lu F, Jiang H, Ding J, Mu J, Valenzuela JG, Ribeiro JM, Su XZ (2007) cDNA sequences reveal considerable gene prediction inaccuracy in the Plasmodium falciparum genome. BMC Genomics 8(1):255

    Article  PubMed  PubMed Central  Google Scholar 

  • Magnani G, Lomazzi M, Peracchi A (2013) Completing the folate biosynthesis pathway in Plasmodium falciparum: p-aminobenzoate is produced by a highly divergent promiscuous aminodeoxychorismate lyase. Biochem J 455(2):149–155

    Article  CAS  PubMed  Google Scholar 

  • Mysinger MM, Carchia M, Irwin JJ, Shoichet BK (2012) Directory of useful decoys, enhanced (DUD-E): better ligands and decoys for better benchmarking. J Med Chem 55(14):6582–6594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • O'Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR (2011) OpenBabel: an open chemical toolbox. Journal of Chemoinformatics 3(1):33

    Article  Google Scholar 

  • Percudani R, Peracchi A (2003) A genomic overview of pyridoxal phosphate dependent enzymes. EMBO Rep 4(9):850–854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pierleoni A, Martelli PL, Fariselli P, Casadio R (2006) BaCelLo: a balanced subcellular localization predictor. Bioinformatics 22(14):e408–e416

    Article  CAS  PubMed  Google Scholar 

  • Pieper U, Eswar N, Braberg H, Madhusudhan MS, Davis FP, Stuart AC, Webb B (2004) MODBASE, a database of annotated comparative protein structure models, and associated resources. Nucleic Acids Res 32:D217–D222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rout S, Warhurst DC, Suar M, Mahapatra RK (2015) In-silico comparative genomics analysis of Plasmodium falciparum for the identification of putative essential genes and therapeutic candidates. J Microbio Meth 109:1–8

    Article  CAS  Google Scholar 

  • Rout S, Mahapatra RK (2016) In silico screening of novel inhibitors of M17 leucine amino peptidase (LAP) of Plasmodium vivax as therapeutic candidate. Biomed & Pharmacoth 82:192–201

    Article  CAS  Google Scholar 

  • Roy A, Kucukural A, Zhang Y (2010) I-TASSER: a unified platform for automated protein structure and function prediction. Nat Protoc 5(4):725–738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sali A, Blundell T (1993) Comparative protein modelling by satisfaction of spatial restraints. J Mol Bio 5:779–815

    Article  Google Scholar 

  • SchuÈttelkopf AW, Van Aalten DM (2004) PRODRG: a tool for high-throughput crystallography of protein–ligand complexes. Acta Crystallograph 60(8):1355–1363

    Google Scholar 

  • Shanmugham B, Pan A (2013) Identification and characterization of potential therapeutic candidates in emerging human pathogen Mycobacterium abscessus: a novel hierarchical in silico approach. PLoS One 8(3):e59126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spangenberg T, Burrows JN, Kowalczyk P, McDonald S, Wells TN, Willis P (2013) The open access malaria box: a drug discovery catalyst for neglected diseases. PLoS One 8(6):e62906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Szklarczyk D, Franceschini A, Kuhn M, Simonovic M, Roth A, Minguez P, Jensen LJ (2011) The STRING database in 2011: functional interaction networks of proteins globally integrated and scored. Nucleic Acids Res 39:D561–D568

    Article  CAS  PubMed  Google Scholar 

  • Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31(2):455–461

    CAS  PubMed  PubMed Central  Google Scholar 

  • Verdonk ML, Cole JC, Hartshorn MJ, Murray CW, Taylor RD (2003) Improved protein–ligand docking using GOLD. Proteins 52(4):609–623

    Article  CAS  PubMed  Google Scholar 

  • Verdonk ML, Berdini V, Hartshorn MJ, Mooij WT, Murray CW, Taylor RD, Watson P (2004) Virtual screening using protein−ligand docking: avoiding artificial enrichment. J Chem Inf Comp Sci 44(3):793–806

    Article  CAS  Google Scholar 

  • Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJ (2005) GROMACS: fast, flexible, and free. J Comput Chem 26(16):1701–1718

    Article  Google Scholar 

  • Vaught A (1996) Graphing with Gnuplot and Xmgr: two graphing packages available under linux. Linux J 1996(28es):7

    Google Scholar 

  • Wass MN, Kelley LA, Sternberg MJ (2010) 3DLigandSite: predicting ligand-binding sites using similar structures. Nucleic Acids Res 38:W469–W473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wolber G, Langer T (2005) LigandScout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters. J Chem Inf Model 45(1):160–169

    Article  CAS  PubMed  Google Scholar 

  • WHO (2015) World malaria report. World Health Organization, Geneva

    Google Scholar 

  • Xu D, Zhang Y (2011) Improving the physical realism and structural accuracy of protein models by a two-step atomic-level energy minimization. Biophys J 101(10):2525–2534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yuthavong Y, Kamchonwongpaisan S, Leartsakulpanich U, Chitnumsub P (2006) Folate metabolism as a source of molecular targets for antimalarials. Future Microbiol 1(1):113–125

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to acknowledge the Bioinformatics Lab Facility of School of Biotechnology, KIIT University, during the course of the work. Miss Subhashree Rout would like to acknowledge DST, Government of India, for the financial support to pursue her PhD work through INSPIRE fellowship. SR and RKM thank Prof. Mrutyunjay Suar, Director of School of Biotechnology in KIIT University, for his encouragement and support during the course of study.

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  1. School of Biotechnology, KIIT University, Bhubaneswar, Orissa, 751024, India

    Subhashree Rout, Namrata Priyadarshini Patra & Rajani Kanta Mahapatra

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  1. Subhashree Rout
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  2. Namrata Priyadarshini Patra
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  3. Rajani Kanta Mahapatra
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Correspondence to Rajani Kanta Mahapatra.

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Rout, S., Patra, N.P. & Mahapatra, R.K. An in silico strategy for identification of novel drug targets against Plasmodium falciparum . Parasitol Res 116, 2539–2559 (2017). https://doi.org/10.1007/s00436-017-5563-2

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