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QSAR modeling and chemical space analysis of antimalarial compounds

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Abstract

Generative topographic mapping (GTM) has been used to visualize and analyze the chemical space of antimalarial compounds as well as to build predictive models linking structure of molecules with their antimalarial activity. For this, a database, including ~3000 molecules tested in one or several of 17 anti-Plasmodium activity assessment protocols, has been compiled by assembling experimental data from in-house and ChEMBL databases. GTM classification models built on subsets corresponding to individual bioassays perform similarly to the earlier reported SVM models. Zones preferentially populated by active and inactive molecules, respectively, clearly emerge in the class landscapes supported by the GTM model. Their analysis resulted in identification of privileged structural motifs of potential antimalarial compounds. Projection of marketed antimalarial drugs on this map allowed us to delineate several areas in the chemical space corresponding to different mechanisms of antimalarial activity. This helped us to make a suggestion about the mode of action of the molecules populating these zones.

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Abbreviations

(Q)SPR/SAR:

(Quantitative) structure–property/structure–activity relationships

(P)RP:

Privileged responsibility patterns

PSM:

Privileged structural motifs

GTM:

Generative topographic map

AD:

Applicability domain

MoA:

Mode of action

References

  1. Barnes KI (2012) Antimalarial drugs and the control and elimination of malaria. In: Staines HM, Krishna S (eds) Treatment and prevention of malaria: antimalarial drug chemistry, action and use. Springer, Basel, p 1

    Google Scholar 

  2. World Health Organization (2016) World malaria report 2015. World Health Organization, Geneva

    Google Scholar 

  3. Snow RW, Guerra CA, Noor AM, Myint HY, Hay SI (2005) Nature 434(7030):214

    Article  CAS  Google Scholar 

  4. Hott A, Tucker MS, Casandra D, Kyle DE (2015) J Antimicrob Chemother 70(10):2787

    Article  CAS  Google Scholar 

  5. Liu H, Ding Y, Walker LA, Doerksen RJ (2015) Chem Res Toxicol 28(2):169

    Article  CAS  Google Scholar 

  6. Blank O, Davioud-Charvet E, Elhabiri M (2012) Antioxid Redox Signal 17(4):544

    Article  CAS  Google Scholar 

  7. Winzeler EA (2008) Nature 455(7214):751

    Article  CAS  Google Scholar 

  8. Jensen M, Mehlhorn H (2009) Parasitol Res 105(3):609

    Article  Google Scholar 

  9. Flannery EL, Fidock DA, Winzeler EA (2013) J Med Chem 56(20):7761

    Article  CAS  Google Scholar 

  10. Plouffe D, Brinker A, McNamara C, Henson K, Kato N, Kuhen K, Nagle A, Adrián F, Matzen JT, Anderson P, Nam T-g, Gray NS, Chatterjee A, Janes J, Yan SF, Trager R, Caldwell JS, Schultz PG, Zhou Y, Winzeler EA (2008) Proc Natl Acad Sci 105(26):9059

    Article  CAS  Google Scholar 

  11. Solomon VR, Puri KS, Srivastava K, Katti BS (2005) Bioorg Med Chem 13:2157–2165

    Article  CAS  Google Scholar 

  12. Gupta MK, Prabhakar YS (2006) J Chem Inf Model 46(1):93

    Article  CAS  Google Scholar 

  13. Deshpande S, Solomon VR, Katti BS, Prabhakar SY (2009) J Enzyme Inhib Med Chem 24:94–104

    Article  CAS  Google Scholar 

  14. Luan F, Xu X, Cordeiro MN, Liu H, Zhang X (2013) Curr Comput Aided Drug Des 9(1):95

    Article  CAS  Google Scholar 

  15. Autreto PAdS, Lavarda FC (2008) Revista do Instituto de Medicina Tropical de São Paulo 50:21

    Article  Google Scholar 

  16. de Campos LJ, de Melo EB (2014) J Mol Graph Model 54:19

    Article  Google Scholar 

  17. Beheshti A, Pourbasheer E, Nekoei M, Vahdani S (2016) J Saudi Chem Soc 20(3):282

    Article  CAS  Google Scholar 

  18. Gamo F-J, Sanz LM, Vidal J, de Cozar C, Alvarez E, Lavandera J-L, Vanderwall DE, Green DVS, Kumar V, Hasan S, Brown JR, Peishoff CE, Cardon LR, Garcia-Bustos JF (2010) Nature 465(7296):305

    Article  CAS  Google Scholar 

  19. Ludin P, Woodcroft B, Ralph SA, Mäser P (2012) Int J Parasitol 2:191

    CAS  Google Scholar 

  20. Spitzmüller A, Mestres J (2013) PLoS Comput Biol 9(10):e1003257

    Article  Google Scholar 

  21. Wawer M, Bajorath J (2011) ACS Med Chem Lett 2(3):201

    Article  CAS  Google Scholar 

  22. Spangenberg T, Burrows JN, Kowalczyk P, McDonald S, Wells TNC, Willis P (2013) PLoS One 8(6):e62906

    Article  CAS  Google Scholar 

  23. Gaulton A, Bellis LJ, Bento AP, Chambers J, Davies M, Hersey A, Light Y, McGlinchey S, Michalovich D, Al-Lazikani B, Overington JP (2011) Nucleic Acids Res 40(D1):D1100

    Article  Google Scholar 

  24. Belorgey D, Antoine Lanfranchi D, Davioud-Charvet E (2013) Curr Pharm Des 19(14):2512

    Article  CAS  Google Scholar 

  25. Elhabiri M, Sidorov P, Cesar-Rodo E, Marcou G, Lanfranchi DA, Davioud-Charvet E, Horvath D, Varnek A (2015) Chem Eur J 21(8):3415

    Article  CAS  Google Scholar 

  26. Sidorov P, Desta I, Chessé M, Horvath D, Marcou G, Varnek A, Davioud-Charvet E, Elhabiri M (2016) ChemMedChem 11(12):1339

    Article  CAS  Google Scholar 

  27. Kireeva N, Baskin, II, Gaspar HA, Horvath D, Marcou G, Varnek A (2012) Mol Inform 31(3–4):301

    Article  CAS  Google Scholar 

  28. Viira B, Gendron T, Lanfranchi D, Cojean S, Horvath D, Marcou G, Varnek A, Maes L, Maran U, Loiseau P, Davioud-Charvet E (2016) Molecules 21(7):853

    Article  Google Scholar 

  29. Horvath D, Marcou G, Varnek A (2013) J Chem Inf Model 53(7):1543

    Article  CAS  Google Scholar 

  30. ChemAxon (2008) Standardizer. ChemAxon, Budapest. http://www.chemaxon.com/jchem/doc/user/standardizer.html. Accessed 20 Feb 2009

  31. ChemAxon (2007) Tautomer Plugin. ChemAxon, Budapest. http://www.chemaxon.com/marvin-archive/4.1.3/marvin/chemaxon/marvin/help/calculator-plugins.html - tautomer. Accessed 20 Oct 2011

  32. Ruggiu F, Marcou G, Varnek A, Horvath D (2010) Mol Inform 29(12):855

    Article  CAS  Google Scholar 

  33. Varnek A, Fourches D, Horvath D, Klimchuk O, Gaudin C, Vayer P, Solov’ev V, Hoonakker F, Tetko Iv, Marcou G (2008) Curr Comput Aided Drug Des 4(3):191

    Article  CAS  Google Scholar 

  34. Varnek A, Fourches D, Hoonakker F, Solov’ev VP (2005) J Comput Aided Mol Des 19(9–10):693

    Article  CAS  Google Scholar 

  35. Laboratoire de Chemoinformatique Strasbourg (2012) Nomenclature of ISIDA fragments

  36. Gaspar HA, Sidorov P, Horvath D, Baskin II, Marcou G, Varnek A (2016) Generative topographic mapping approach to chemical space analysis. In: Frontiers in molecular design and chemical information science—Herman Skolnik Award Symposium 2015: Jürgen Bajorath, vol 1222. American Chemical Society, p 211

  37. Gaspar H, Marcou G, Horvath D, Arault A, Lozano S, Vayer P, Varnek A (2013) J Chem Inf Model 53(12):3318

    Article  CAS  Google Scholar 

  38. Gaspar HA, Baskin II, Marcou G, Horvath D, Varnek A (2015) Mol Inform 34(6–7):348

    Article  CAS  Google Scholar 

  39. Sidorov P, Gaspar H, Marcou G, Varnek A, Horvath D (2015) J Comput Aided Mol Des 29(12):1087

    Article  CAS  Google Scholar 

  40. Horvath D, Brown BJ, Marcou G, Varnek A (2014) Challenges 5(2)

  41. Klimenko K, Marcou G, Horvath D, Varnek A (2016) J Chem Inf Model 56(8):1438

    Article  CAS  Google Scholar 

  42. Baell JB, Holloway GA (2010) J Med Chem 53(7):2719

    Article  CAS  Google Scholar 

  43. Müller T, Johann L, Jannack B, Bruckner M, Lanfranchi DA, Bauer H, Sanchez C, Yardley V, Deregnaucourt C, Schrevel J, Lanzer M, Schirmer RH, Davioud-Charvet E (2011) J Am Chem Soc 133(30):11557

    Article  Google Scholar 

  44. Lanfranchi DA, Cesar-Rodo E, Bertrand B, Huang H-H, Day L, Johann L, Elhabiri M, Becker K, Williams DL, Davioud-Charvet E (2012) Org Biomol Chem 10(31):6375

    Article  CAS  Google Scholar 

  45. Guiguemde WA, Shelat AA, Bouck D, Duffy S, Crowther GJ, Davis PH, Smithson DC, Connelly M, Clark J, Zhu F, Jiménez-Díaz MB, Martinez MS, Wilson EB, Tripathi AK, Gut J, Sharlow ER, Bathurst I, El Mazouni F, Fowble JW, Forquer I, McGinley PL, Castro S, Angulo-Barturen I, Ferrer S, Rosenthal PJ, Derisi JL, Sullivan DJ, Lazo JS, Roos DS, Riscoe MK, Phillips MA, Rathod PK, Van Voorhis WC, Avery VM, Guy RK (2010) Nature 465(7296):311

    Article  CAS  Google Scholar 

  46. Krishna S, Staines HM (2012) Non-antifolate antibiotics: clindamycin, doxycycline, azithromycin and fosmidomycin. In: Staines HM, Krishna S (eds) Treatment and prevention of malaria: antimalarial drug chemistry, action and use. Springer, Basel, p 141

    Google Scholar 

  47. Olliaro P (2001) Pharmacol Ther 89(2):207

    Article  CAS  Google Scholar 

  48. O’Neill PM, Barton VE, Ward SA, Chadwick J (2012) 4-Aminoquinolines: chloroquine, amodiaquine and next-generation analogues. In: Staines HM, Krishna S (eds) Treatment and prevention of malaria: antimalarial drug chemistry, action and use. Springer, Basel, p 19

    Google Scholar 

  49. Vaidya AB (2012) Naphthoquinones: atovaquone, and other antimalarials targeting mitochondrial functions. In: Staines HM, Krishna S (eds) Treatment and prevention of malaria: antimalarial drug chemistry, action and use. Springer, Basel, p 127

    Google Scholar 

  50. Baird K (2015) Pathog Glob Health 109(3):93

    Article  CAS  Google Scholar 

  51. Hill DR, Baird JK, Parise ME, Lewis LS, Ryan ET, Magill AJ (2006) Am J Trop Med Hyg 75(3):402

    CAS  Google Scholar 

  52. Nzila A (2012) Antifolates: pyrimethamine, proguanil, sulphadoxine and dapsone. In: Staines HM, Krishna S (eds) Treatment and prevention of malaria: antimalarial drug chemistry, action and use. Springer, Basel, p 113

    Google Scholar 

Download references

Acknowledgements

The Laboratory of Chemoinformatics wishes to thank the High Performance Computing centers of the University of Strasbourg, France and the Babes-Bolyai University of Cluj, Romania for supplied computer power, and assistance. P.S. thanks Program of Competitive Growth of Kazan Federal University for support. B.V. is grateful to the European Social Fund (Grant 30.1-9.1/575, mediated by Archimedes Foundation, http://www.archimedes.ee, DoRa T6 subprogram, internationalization and mobility support scheme, for the mobility stipend) and the COST Action CM1307 for three short-term scientific missions (STSM) fellowships to Strasbourg to perform data analysis, curation and database creation, as well as the cheminformatics study. B.V. and U.M. are also grateful for financial support from the Estonian Ministry of Education and Research (Grant IUT34-14). This work was partly supported by the International Center for Frontier Research in Chemistry in Strasbourg (icFRC Innovation 2015 Program, project entitled “Computer-Aided Design of Novel Antimalarial Naphthoquinones (CAD-NQ)”, A.V., E.D.-C.) and the Laboratoire d’Excellence ParaFrap (grant LabEx ParaFrap ANR-11-LABX-0024, E.D.-C.).

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Authors and Affiliations

  1. Laboratoire de Chemoinformatique, UMR7140 CNRS-Université de Strasbourg, 1 rue Blaise Pascal, 67000, Strasbourg, France

    Pavel Sidorov, Gilles Marcou, Dragos Horvath & Alexandre Varnek

  2. Laboratory of Chemoinfomatics, Butlerov Institute of Chemistry, Kazan Federal University, Kazan, Russia, 420008

    Pavel Sidorov

  3. Institute of Chemistry, University of Tartu, 50411, Tartu, Estonia

    Birgit Viira & Uko Maran

  4. Bioorganic and Medicinal Chemistry Team, European School of Chemistry, Polymers and Materials (ECPM), UMR 7509 CNRS—University of Strasbourg, 25, rue Becquerel, 67087, Strasbourg, France

    Elisabeth Davioud-Charvet

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  1. Pavel Sidorov
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  2. Birgit Viira
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  3. Elisabeth Davioud-Charvet
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  4. Uko Maran
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  5. Gilles Marcou
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Correspondence to Dragos Horvath or Alexandre Varnek.

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Sidorov, P., Viira, B., Davioud-Charvet, E. et al. QSAR modeling and chemical space analysis of antimalarial compounds. J Comput Aided Mol Des 31, 441–451 (2017). https://doi.org/10.1007/s10822-017-0019-4

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