Skip to main content

Advertisement

Springer Nature Link
Log in

Bond-based linear indices in QSAR: computational discovery of novel anti-trichomonal compounds

  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Abstract

Trichomonas vaginalis (Tv) is the causative agent of the most common, non-viral, sexually transmitted disease in women and men worldwide. Since 1959, metronidazole (MTZ) has been the drug of choice in the systemic treatment of trichomoniasis. However, resistance to MTZ in some patients and the great cost associated with the development of new trichomonacidals make necessary the development of computational methods that shorten the drug discovery pipeline. Toward this end, bond-based linear indices, new TOMOCOMD-CARDD molecular descriptors, and linear discriminant analysis were used to discover novel trichomonacidal chemicals. The obtained models, using non-stochastic and stochastic indices, are able to classify correctly 89.01% (87.50%) and 82.42% (84.38%) of the chemicals in the training (test) sets, respectively. These results validate the models for their use in the ligand-based virtual screening. In addition, they show large Matthews’ correlation coefficients (C) of 0.78 (0.71) and 0.65 (0.65) for the training (test) sets, correspondingly. The result of predictions on the 10% full-out cross-validation test also evidences the robustness of the obtained models. Later, both models are applied to the virtual screening of 12 compounds already proved against Tv. As a result, they correctly classify 10 out of 12 (83.33%) and 9 out of 12 (75.00%) of the chemicals, respectively; which is the most important criterion for validating the models. Besides, these classification functions are applied to a library of seven chemicals in order to find novel antitrichomonal agents. These compounds are synthesized and tested for in vitro activity against Tv. As a result, experimental observations approached to theoretical predictions, since it was obtained a correct classification of 85.71% (6 out of 7) of the chemicals. Moreover, out of the seven compounds that are screened, synthesized and biologically assayed, six compounds (VA7-34, VA7-35, VA7-37, VA7-38, VA7-68, VA7-70) show pronounced cytocidal activity at the concentration of 100 μg/ml at 24 h (48 h) within the range of 98.66%–100% (99.40%–100%), while only two molecules (chemicals VA7-37 and VA7-38) show high cytocidal activity at the concentration of 10 μg/ml at 24 h (48 h): 98.38% (94.23%) and 97.59% (98.10%), correspondingly. The LDA-assisted QSAR models presented here could significantly reduce the number of synthesized and tested compounds and could increase the chance of finding new chemical entities with anti-trichomonal activity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Krieger JN (2000) Sex Transm Dis 27:241

    Article  CAS  Google Scholar 

  2. Petrin D, Delgaty K, Bhatt R, Garber G (1998) Clin Microbiol Rev 11:300

    CAS  Google Scholar 

  3. World-Health-Organization (1995) An overview of selected curable sexually transmitted diseases. World Health Organization, Geneva Switzerland, p 2

    Google Scholar 

  4. Cosar C, Julou L (1959) Ann Inst Pasteur 96:238

    CAS  Google Scholar 

  5. Centers for Disease Control and Prevention (1993) Morb Mortal Wkly Rep 42(RR-14) 70

    Google Scholar 

  6. Knight R (1980) J Antimicrob Chemother 6:577

    Article  CAS  Google Scholar 

  7. Gillette H, Schmid GP, Moswe D (1985) Metronidazole-resistant Trichomonas vaginalis, a case series, Denver, 1999

  8. Lumsden WHR, Robertson DHH, Heyworth R, Harrison C (1988) Genitourin Med 64:217

    CAS  Google Scholar 

  9. Narcisi EM, Secor WE (1996) Antimicrob Agents Chemother 40:1121

    CAS  Google Scholar 

  10. Narcisi EM, Secor WE (1996) Antimicrob Agents Chemother 40:1121

    CAS  Google Scholar 

  11. Houang ET, Ahmet Z, Lawrence AG (1997) Sex Transm Dis 24:116

    Article  CAS  Google Scholar 

  12. Pattman RS, Sprott MS, Kerns AM, Earnshaw M (1989) Genitourin Med 65:274

    CAS  Google Scholar 

  13. Wong CA, Wilson PD, Chew TA (1990) Aust N Z J Obstet Gynaecol 30:169

    Article  CAS  Google Scholar 

  14. Livengood CHI, Lossick JG (1991) Obstet Gynecol 78:954

    Google Scholar 

  15. Watson PG, Pattman RS (1996) Int J STD AIDS 7:296

    Article  CAS  Google Scholar 

  16. Nyirjesy P, Sobel JD, Weitz MV (1998) Clin Infect Dis 26:986

    Article  CAS  Google Scholar 

  17. Nyirjesy P, Weitz MV, Gelone SP, Fekete T (1995) Lancet 346:1110

    Article  CAS  Google Scholar 

  18. Estrada E, Peña A (2000) Bioorg Med Chem 8:2755

    Article  CAS  Google Scholar 

  19. Estrada E, Uriarte E, Montero A, Teijeira M, Santana L, De Clercq E (2000) J Med Chem 43:1975

    Article  CAS  Google Scholar 

  20. Marrero-Ponce Y, Romero V, TOMOCOMD software, Central University of Las Villas TOMOCOMD (TOpological MOlecular COMputer Design) for Windows, version 1.0 is a preliminary experimental version; in future a professional version can be obtained upon request to Y. Marrero: yovanimp@uclv.edu.cu or ymarrero77@yahoo.es.

  21. Marrero-Ponce Y (2003) Molecules 8:687

    Google Scholar 

  22. Marrero-Ponce Y (2004) J Chem Inf Comput Sci 44:2010

    Article  CAS  Google Scholar 

  23. Marrero-Ponce Y (2004) Bioorg Med Chem 12:6351

    Article  CAS  Google Scholar 

  24. Marrero-Ponce Y, Castillo-Garit JA, Torrens F, Romero-Zaldivar V, Castro E (2004) Molecules 9:1100

    Google Scholar 

  25. Marrero-Ponce Y, Díaz HG, Romero V, Torrens F, Castro EA (2004) Bioorg Med Chem 12:5331

    Article  CAS  Google Scholar 

  26. Marrero-Ponce Y, Cabrera MA, Romero V, Ofori E, Montero LA (2003) Int J Mol Sci 4:512

    Google Scholar 

  27. Marrero-Ponce Y, Cabrera MA, Romero V, González DH, Torrens F (2004) J Pharm Pharmaceut Sci 7:186

    Google Scholar 

  28. Marrero-Ponce Y, Cabrera MA, Romero-Zaldivar V, Bermejo M, Siverio D, Torrens F (2005) Internet Electrón J Mol Des 4:124

    Google Scholar 

  29. Marrero-Ponce Y, Castillo-Garit JA, Olazabal E, Serrano HS, Morales A, Castanedo N, Ibarra-Velarde F, Huesca-Guillen A, Sanchez AM, Torrens F, Castro EA (2005) Bioorg Med Chem 13:1005

    Article  CAS  Google Scholar 

  30. Marrero-Ponce Y, Castillo-Garit JA, Olazabal E, Serrano HS, Morales A, Castanedo N, Ibarra-Velarde F, Huesca-Guillen A, Jorge E, del Valle A, Torrens F, Castro EA (2004) J Comput Aided Mol Des 18:615

    Article  CAS  Google Scholar 

  31. Marrero-Ponce Y, Huesca-Guillen A, Ibarra-Velarde F (2005) J Mol Struct (Theochem) 717:67

    Article  CAS  Google Scholar 

  32. Marrero-Ponce Y, Montero-Torres A, Zaldivar CR, Veitia MI, Perez MM, Sanchez RN (2005) Bioorg Med Chem 13:1293

    Article  CAS  Google Scholar 

  33. Marrero-Ponce Y, Medina-Marrero R, Torrens F, Martinez Y, Romero-Zaldivar V, Castro EA (2005) Bioorg Med Chem 13:2881

    Article  CAS  Google Scholar 

  34. Marrero-Ponce Y, Medina-Marrero R, Martinez Y, Torrens F, Romero-Zaldivar V, Castro EA (2006) J Mol Mod 12:255

    Article  CAS  Google Scholar 

  35. Marrero-Ponce Y, Nodarse D, González HD, Ramos de Armas R, Romero-Zaldivar V, Torrens F, Castro E (2004) Int J Mol Sci 5:276

    Google Scholar 

  36. Marrero-Ponce Y, Castillo-Garit JA, Nodarse D (2005) Bioorg Med Chem 13:3397

    Article  CAS  Google Scholar 

  37. Marrero-Ponce Y, Medina R, Castro EA, de Armas R, González H, Romero V, Torrens F (2004) Molecules 9:1124

    Google Scholar 

  38. Marrero-Ponce Y, Medina-Marrero R, Castillo-Garit JA, Romero-Zaldivar V, Torrens F, Castro EA (2005) Bioorg Med Chem 13:3003

    Article  CAS  Google Scholar 

  39. Marrero-Ponce Y, Torrens F (2006) J Comp-Aided Mol Des 20:685

    Article  CAS  Google Scholar 

  40. Casañola-Martin GM, Khan MTH, Marrero-Ponce Y, Ather A, Sultan S, Torrens F, Rotondo R (2007) Bioorg Med Chem 15:1483

    Article  CAS  Google Scholar 

  41. Todeschini R, Consonni V (2000) Handbook of molecular descriptors. Wiley-VCH, Germany

    Google Scholar 

  42. Estrada E (1996) J Chem Inf Comput Sci 36:844

    Article  CAS  Google Scholar 

  43. Estrada E, Molina E (2001) J Mol Graph Model 20:54

    Article  CAS  Google Scholar 

  44. Estrada E (1995) J Chem Inf Comput Sci 35:31

    Article  CAS  Google Scholar 

  45. Estrada E, Guevara N, Gutman I (1998) J Chem Inf Comput Sci 38:428

    Article  CAS  Google Scholar 

  46. Estrada E (1999) J Chem Inf Comput Sci 39:1042

    Article  CAS  Google Scholar 

  47. Edwards CH, Penney DE (1988) Elementary linear algebra. Prentice-Hall, Englewood Cliffs, New Jersey, USA

    Google Scholar 

  48. Marrero Ponce Y (2004) J Chem Inf Comput Sci 44:2010

    Article  CAS  Google Scholar 

  49. Estrada E, Vilar S, Uriarte E, Gutierrez Y (2002) J Chem Inf Comput Sci 42:1194

    Article  CAS  Google Scholar 

  50. Estrada E, Peña A, Garcia-Domenech R (1998) J Comput Aided Mol Des 12:583

    Article  CAS  Google Scholar 

  51. Potapov VM (1978) Stereochemistry. Mir, Moscow

    Google Scholar 

  52. Wang R, Gao Y, Lai L (2000) Perspect Drug Dis Des 19:47

    Article  CAS  Google Scholar 

  53. Ertl P, Rohde B, Selzer P (2000) J Med Chem 43:3714

    Article  CAS  Google Scholar 

  54. Ghose AK, Crippen GM (1987) J Chem Inf Comput Sci 27:21

    CAS  Google Scholar 

  55. Miller KJ (1990) J Am Chem Soc 112:8533

    Article  CAS  Google Scholar 

  56. Gasteiger J, Marsili M (1978) Tetrahedron Lett 19:3181

    Article  Google Scholar 

  57. Pauling L (1939) The nature of chemical bond. Cornell University Press, Ithaca (New York)

    Google Scholar 

  58. Browder A (1996) Mathematical analysis. An introduction. Springer-Verlag, New York

    Google Scholar 

  59. Axler S (1996) Linear algebra done right. Springer-Verlag, New York

    Google Scholar 

  60. Daudel R, Lefebre R, Moser C (1984) Quantum chemistry: methods and applications. Wiley, New York

    Google Scholar 

  61. Klein DJ (2003) Internet Electron J Mol Des 2:814

    CAS  Google Scholar 

  62. Todeschini R, Gramatica P (1998) Perspect Drug Dis Des 9–11:355

    Article  Google Scholar 

  63. Consonni V, Todeschini R, Pavan M (2002) J Chem Inf Comput Sci 42:682

    Article  CAS  Google Scholar 

  64. Kier LB, Hall LH (1986) Molecular connectivity in structure–activity analysis. Research Studies Press, Letchworth, UK

    Google Scholar 

  65. Negwer M (1987) Organic-chemical drugs and their synonyms. Akademie-Verlag, Berlin

    Google Scholar 

  66. Budavari S, O’Neil M, Ann Smith, Heckelman P, Obenchain J (1999) The Merck Index on CD-ROM. Chapman & Hall and Merck & Co., Inc

  67. van de Waterbeemd H (1995) In: van Waterbeemd H (ed) Chemometric methods in molecular design. VCH Publishers, Weinheim, p 265

    Google Scholar 

  68. STATISTICA (data analysis software system) vs 6.0.

  69. Estrada E, Patlewicz G (2004) Croat Chim Acta 77:203

    CAS  Google Scholar 

  70. Topliss JG, Edwards RP (1979) J Med Chem 22:1238

    Article  CAS  Google Scholar 

  71. Wold S, Erikson L (1995) In: van de Waterbeemd H (ed) VCH Publishers, New York, p 309

  72. Baldi P, Brunak S, Chauvin Y, Andersen CA, Nielsen H (2000) Bioinformatics 16:412

    Article  CAS  Google Scholar 

  73. Kouznetsov VV, Rivero CJ, Ochoa PC, Stashenko E, Martínez JR, Montero PD, Nogal RJJ, Fernández PC, Muelas SS, Gómez BA, Bahsas A, Amaro L (2005) J Arch Pharm 1:338

    Google Scholar 

  74. Kouznetsov VV, Vargas MLY, Tibaduiza B, Ochoa C, Montero PD, Nogal RJJ, Fernández C, Muelas S, Gómez A, Bahsas A, Amaro-Luis J (2004) J Arch Pharm 337:127

    Article  CAS  Google Scholar 

  75. Gálvez J, Garcia-Domenech R, de Julián-Ortiz JV, Soler R (1995) J Chem Inf Comput Sci 35:272

    Article  Google Scholar 

  76. Cercos-del-Pozo RA, Pérez-Giménez F, Salabert-Salvador MT, Garcia-March FJ (2000) J Chem Inf Comput Sci 40:178

    Article  CAS  Google Scholar 

  77. Gálvez J, García R, Salabert MT, Soler R (1994) J Chem Inf Comput Sci 34:520

    Article  Google Scholar 

  78. Johnson RA, Wichern DW (1988) Applied multivariate statistical analysis. Prentice-Hall, New Jersey

    Google Scholar 

  79. Golbraikh A, Tropsha A (2002) J Mol Graph Model 20:269

    Article  CAS  Google Scholar 

  80. Rose K, Hall LH, Kier LB (2002) J Chem Inf Comput Sci 42:651

    Article  CAS  Google Scholar 

  81. Mc Farland JW, Gans DJ (1995) In: Waterbeemd H (ed) Chemometric methods in molecular design. VCH Publishers, New York, p 295

    Google Scholar 

  82. Estrada E, Uriarte E (2001) Curr Med Chem 8:1573

    CAS  Google Scholar 

  83. Gavini E, Juliano C, Mulé A, Pirisino G, Murineddu G, Pinna A (2000) Arch Pharm (Weinheim) 333:341

    Article  CAS  Google Scholar 

  84. Ochoa A, Pérez E, Pérez R, Suárez M, Ochoa E, Rodríguez H, Gómez A, Muelas S, Nogal RJJ, Martínez RA (1999) Arzneim Forsch 49:764

    CAS  Google Scholar 

  85. Kouznetsov V, Rodríguez W, Stashenko E, Ochoa C, Vega C, Rolón M, Montero PD, Escario JA, Gómez BA (2004) J Heterocyclic Chem 41:1

    Article  Google Scholar 

  86. Watson C (2003) Biosilico 1:83

    Article  Google Scholar 

  87. Lajiness MS (1990) In: Rouvray DH (ed) Computational chemical graph theory. Nova Science, New York, p 299

    Google Scholar 

  88. Walters WP, Stahl MT, Murcko MA (1998) Drug Discov Today 3:160

    Article  CAS  Google Scholar 

  89. Castro S, Chicharro R, Arán VJ (2002) J Chem Soc, Perkin Trans 1:790

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors wish to express their gratitude to Prof. Dr. Jorge Gálvez for his attention to this work and valuable suggestions. Yovani Marrero-Ponce (M.-P. Y) acknowledges the Valencia University for kind hospitality during the second semester of 2007. M.-P. Y thanks are given to the international relationships of Valencia University, (Spain) for partial financial support as well as the program ‘Estades Temporals per an Investigadors Convidats’ for a fellowship to work at Valencia University. Some authors’ thanks support from Spanish MEC (Project Reference: SAF2006-04698). Finally, F.T. thanks support from Spanish MEC DGI (Project No. CTQ2004-07768-C02-01/BQU) and Generalitat Valenciana (DGEUI INF01-051 and INFRA03-047, and OCYT GRUPOS03-173). Last but not least, Yovani Marrero-Ponce would like to express thanks for the partial support received from the project entitled Strengthening postgraduate education and research in Pharmaceutical Sciences. This project is funded by the Flemish Interuniversity Council (VLIR) of Belgium.

Author information

Authors and Affiliations

  1. Faculty of Chemistry-Pharmacy, Unit of Computer-Aided Molecular “Biosilico” Discovery and Bioinformatic Research (CAMD-BIR Unit), Central University of Las Villas, Santa Clara, 54830, Villa Clara, Cuba

    Yovani Marrero-Ponce, Alfredo Meneses-Marcel, Oscar M. Rivera-Borroto & Alina Montero

  2. Institut Universitari de Ciència Molecular, Universitat de València, Edifici d’Instituts de Paterna, P.O. Box 22085, Valencia, 46071, Spain

    Yovani Marrero-Ponce & Francisco Torrens

  3. Departamento de Química Física, Facultad de Farmacia, Unidad de Investigación de Diseño de Fármacos y Conectividad Molecular, Universitat de València, Valencia, Spain

    Yovani Marrero-Ponce, Ramón García-Domenech & Jesus Vicente De Julián-Ortiz

  4. Departamento de Parasitología, Facultad de Farmacia, UCM, Pza. Ramón y Cajal s/n, Madrid, 28040, Spain

    Alfredo Meneses-Marcel, José Antonio Escario, Alicia Gómez Barrio, David Montero Pereira & Juan José Nogal

  5. Faculty of Mathemathics, Physics & Computer Science, Center of Studies on Informatics, Central University of Las Villas, Santa Clara, 54830, Villa Clara, Cuba

    Oscar M. Rivera-Borroto & Ricardo Grau

  6. Institut für Chemie, Universität Rostock, Abteilung für Organische Chemie, Albert-Einstein-Straße 3a, 18059, Rostock, Germany

    Christian Vogel

  7. Instituto de Química Médica, CSIC, c/ Juan de la Cierva 3, Madrid, 28006, Spain

    Vicente J. Arán

Authors
  1. Yovani Marrero-Ponce
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Alfredo Meneses-Marcel
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Oscar M. Rivera-Borroto
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Ramón García-Domenech
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Jesus Vicente De Julián-Ortiz
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Alina Montero
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. José Antonio Escario
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Alicia Gómez Barrio
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. David Montero Pereira
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Juan José Nogal
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Ricardo Grau
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Francisco Torrens
    View author publications

    You can also search for this author inPubMed Google Scholar

  13. Christian Vogel
    View author publications

    You can also search for this author inPubMed Google Scholar

  14. Vicente J. Arán
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Yovani Marrero-Ponce.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Marrero-Ponce, Y., Meneses-Marcel, A., Rivera-Borroto, O.M. et al. Bond-based linear indices in QSAR: computational discovery of novel anti-trichomonal compounds. J Comput Aided Mol Des 22, 523–540 (2008). https://doi.org/10.1007/s10822-008-9171-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-008-9171-1

Keywords