Journal of Computer-Aided Molecular Design

, Volume 21, Issue 4, pp 167–188 | Cite as

Bond-based 2D TOMOCOMD-CARDD approach for drug discovery: aiding decision-making in ‘in silico’ selection of new lead tyrosinase inhibitors

  • Yovani Marrero-Ponce
  • Mahmud Tareq Hassan Khan
  • Gerardo M. Casañola-Martín
  • Arjumand Ather
  • Mukhlis N. Sultankhodzhaev
  • Ramón García-Domenech
  • Francisco Torrens
  • Richard Rotondo
Original Paper


In this paper, we present a new set of bond-level TOMOCOMD-CARDD molecular descriptors (MDs), the bond-based bilinear indices, based on a bilinear map similar to those defined in linear algebra. These novel MDs are used here in Quantitative Structure–Activity Relationship (QSAR) studies of tyrosinase inhibitors, for finding functions that discriminate between the tyrosinase inhibitor compounds and inactive ones. In total 14 models were obtained and the best two discriminant functions (Eqs. 32 and 33) shown globally good classification of 91.00% and 90.17%, respectively, in the training set. The test set had accuracies of 93.33% and 88.89% for the models 32 and 33, correspondingly. A simulated virtual screening was also carried out to prove the quality of the determined models. In a final step, the fitted models were used in the biosilico identification of new synthesized tetraketones, where a good agreement could be observed between the theoretical and experimental results. Four compounds of the novel bioactive chemicals discovered as tyrosinase inhibitors: TK10 (IC50 = 2.09 μM), TK11 (IC50 = 2.61 μM), TK21 (IC50 = 2.06 μM), TK23 (IC50 = 3.19 μM), showed more potent activity than l-mimose (IC50 = 3.68 μM). Besides, for this study a heterogeneous database of tyrosinase inhibitors was collected, and could be a useful tool for the scientist in the domain of tyrosinase enzyme researches. The current report could help to shed some clues in the identification of new chemicals that inhibits enzyme tyrosinase, for entering in the pipeline of drug discovery development.


TOMOCOMD-CARDD software Non-stochastic and stochastic bond-based bilinear indices LDA-based QSAR model Tyrosinase inhibitor TetraKetones Virtual screening Biosilico identification Experimental results 



One of the authors (M-P. Y) thanks the program ‘Estades Temporals per a Investigadors Convidats’ for a fellowship to work at Valencia University (2006–2007). M-P. Y thanks are also given to the Generalitat Valenciana, (Spain) for partial financial support as well as support from Spanish MEC (Project Reference: SAF2006-04698). MTHK is the recipient of a grant from MCBN-UNESCO (grant no. 1056), and fellowships from CIB (Italy) and Associasione Veneta per la Lotta alla Talassemia (AVTL, Italy). F. T. acknowledges financial support from the Spanish MEC DGI (Project No.CTQ2004-07768-C02-01/BQU) and Generalitat Valenciana (DGEUI INF01-051 and INFRA03-047, and OCYT GRUPOS03-173.

Supplementary material

10822_2006_9094_MOESM1_ESM.pdf (575 kb)
ESM 1 (PDF 576 KB)


  1. 1.
    Robb DA (1984) Copper proteins and copper enzymes. CRC Press, Boca Raton, FLGoogle Scholar
  2. 2.
    Baurin N, Arnoult E, Scior T, Do QT, Bernard P (2002) J Ethnopharmacol 82:155CrossRefGoogle Scholar
  3. 3.
    Prota G (1988) Med Res Rev 8:525CrossRefGoogle Scholar
  4. 4.
    Prota G (1992) Melanins and melanogenesis. Academic Press, San Diego, CAGoogle Scholar
  5. 5.
    Riley PA (1996) In: Hori Y, Hearing VJ, Nakayama J (eds) Melanogenesis and malignant melanoma: biochemistry, cell biology, molecular biology, pathophysiology, diagnosis and treatment. Elsevier, AmsterdamGoogle Scholar
  6. 6.
    Riley PA (2003) Pigment Cell Res 16:548CrossRefGoogle Scholar
  7. 7.
    Fitzpatrick TB, Seji M, McGugan AD (1961) New Engl J Med 265:374CrossRefGoogle Scholar
  8. 8.
    Maeda K, Fukuda M (1996) J Pharmacol Exp Ther 276:765Google Scholar
  9. 9.
    Li W, Kubo I (2004) Bioorg Med Chem 12:701CrossRefGoogle Scholar
  10. 10.
    Casañola-Martin GM, Khan MT, Marrero-Ponce Y, Ather A, Sultankhodzhaev MN, Torrens F (2006) Bioorg Med Chem Lett 16:324CrossRefGoogle Scholar
  11. 11.
    Marrero-Ponce Y, Khan MTH, Casañola-Martín GM, Ather A, Sultankhodzhaev MN, Torrens F (2006) QSAR Comb Sci DOI: 10.1002/qsar.200610156Google Scholar
  12. 12.
    Marrero-Ponce Y (2003) Molecules 8:687Google Scholar
  13. 13.
    Marrero-Ponce Y, Huesca-Guillen A, Ibarra-Velarde F (2005) J Mol Struct (Theochem) 717:67CrossRefGoogle Scholar
  14. 14.
    Meneses-Marcel A, Marrero-Ponce Y, Machado-Tugores Y, Montero-Torres A, Pereira DM, Escario JA, Nogal-Ruiz JJ, Ochoa C, Aran VJ, Martinez-Fernandez AR, Garcia Sanchez RN (2005) Bioorg Med Chem Lett 15:3838CrossRefGoogle Scholar
  15. 15.
    Vega MC, Montero-Torres A, Marrero-Ponce Y, Rolon M, Gomez-Barrio A, Escario JA, Aran VJ, Nogal JJ, Meneses-Marcel A, Torrens F (2006) Bioorg Med Chem Lett 16:1898CrossRefGoogle Scholar
  16. 16.
    Marrero-Ponce Y, Medina-Marrero R, Martinez Y, Torrens F, Romero-Zaldivar V, Castro EA (2006) J Mol Mod 12:255CrossRefGoogle Scholar
  17. 17.
    Marrero-Ponce Y, Nodarse D, González HD, Ramos de Armas R, Romero-Zaldivar V, Torrens F, Castro E (2004) Int J Mol Sci 5:276Google Scholar
  18. 18.
    Marrero Ponce Y, Castillo Garit JA, Nodarse D (2005) Bioorg Med Chem 13:3397CrossRefGoogle Scholar
  19. 19.
    Marrero-Ponce Y, Iyarreta-Veitia M, Montero-Torres A, Romero-Zaldivar C, Brandt CA, Avila PE, Kirchgatter K, Machado Y (2005) J Chem Inf Model 45:1082CrossRefGoogle Scholar
  20. 20.
    Marrero-Ponce Y, Romero V, TOMOCOMD software, Central University of Las Villas (2002) 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: or ymarrero77@yahoo.esGoogle Scholar
  21. 21.
    Rouvray DH (1976) In: Balaban AT (ed) Chemical applications of graph theory. Academic Press, London, pp 180–181Google Scholar
  22. 22.
    Trinajstić N (1983) Chemical graph theory. CRC Press, Boca Raton FLGoogle Scholar
  23. 23.
    Estrada E (1995) J Chem Inf Comput Sci 35:31CrossRefGoogle Scholar
  24. 24.
    Estrada E, Ramirez A (1996) J Chem Inf Comput Sci 36:837CrossRefGoogle Scholar
  25. 25.
    Estrada E (1996) J Chem Inf Comput Sci 36:844CrossRefGoogle Scholar
  26. 26.
    Estrada E, Guevara N, Gutman I (1998) J Chem Inf Comput Sci 38:428CrossRefGoogle Scholar
  27. 27.
    Estrada E (1999) J Chem Inf Comput Sci 39:1042CrossRefGoogle Scholar
  28. 28.
    Estrada E, Molina E (2001) J Mol Graph Model 20:54CrossRefGoogle Scholar
  29. 29.
    Todeschini R, Consonni V (2000) Handbook of molecular descriptors. Wiley-VCH, GermanyGoogle Scholar
  30. 30.
    Ivanciuc O, Balaban AT (1999) In: Devillers J, Balaban AT (eds) Topological indices and related descriptors in QSAR and QSPR. Gordon and Breach, The Netherlands, 73 pGoogle Scholar
  31. 31.
    Edwards CH, Penney DE (1988) Elementary linear algebra. Prentice-Hall, Englewood Cliffs, New Jersey, USAGoogle Scholar
  32. 32.
    Marrero-Ponce Y (2004) Bioorg Med Chem 12:6351CrossRefGoogle Scholar
  33. 33.
    Marrero-Ponce Y, Castillo-Garit JA, Olazabal E, Serrano HS, Morales A, Castañedo N, Ibarra-Velarde F, Huesca-Guillen A, Jorge E, del Valle A, Torrens F, Castro EA (2004) J Comput Aided Mol Des 18:615CrossRefGoogle Scholar
  34. 34.
    Marrero-Ponce Y, Medina-Marrero R, Torrens F, Martinez Y, Romero-Zaldivar V, Castro EA (2005) Bioorg Med Chem 13:2881CrossRefGoogle Scholar
  35. 35.
    Marrero-Ponce Y, Díaz HG, Romero V, Torrens F, Castro EA (2004) Bioorg Med Chem 12:5331CrossRefGoogle Scholar
  36. 36.
    Marrero-Ponce Y, Cabrera MA, Romero V, Ofori E, Montero LA (2003) Int J Mol Sci 4:512Google Scholar
  37. 37.
    Marrero-Ponce Y, Cabrera MA, Romero V, González DH, Torrens F (2004) J Pharm Pharmaceut Sci 7:186Google Scholar
  38. 38.
    Marrero-Ponce Y, Cabrera MA, Romero-Zaldivar V, Bermejo M, Siverio D, Torrens F (2005) Internet Electron J Mol Des 4:124Google Scholar
  39. 39.
    Marrero-Ponce Y, Medina R, Castro EA, de Armas R, González H, Romero V, Torrens F (2004) Molecules 9:1124Google Scholar
  40. 40.
    Marrero Ponce Y (2004) J Chem Inf Comput Sci 44:2010CrossRefGoogle Scholar
  41. 41.
    Marrero-Ponce Y, Castillo-Garit JA, Torrens F, Romero-Zaldivar V, Castro E (2004) Molecules 9:1100Google Scholar
  42. 42.
    Marrero-Ponce Y, Montero-Torres A, Zaldivar CR, Veitia MI, Perez MM, Sanchez RN (2005) Bioorg Med Chem 13:1293CrossRefGoogle Scholar
  43. 43.
    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 13:1005CrossRefGoogle Scholar
  44. 44.
    Marrero-Ponce Y, Castillo-Garit JA (2005) J Comput Aided Mol Des 19:369CrossRefGoogle Scholar
  45. 45.
    Estrada E, Vilar S, Uriarte E, Gutierrez Y (2002) J Chem Inf Comput Sci 42:1194CrossRefGoogle Scholar
  46. 46.
    Estrada E, Uriarte E, Montero A, Teijeira M, Santana L, De Clercq E (2000) J Med Chem 43:1975CrossRefGoogle Scholar
  47. 47.
    Estrada E, Peña A, Garcia-Domenech R (1998) J Comput Aided Mol Des 12:583CrossRefGoogle Scholar
  48. 48.
    Potapov VM (1978) Stereochemistry. Mir MoscowGoogle Scholar
  49. 49.
    Wang R, Gao Y, Lai L (2000) Perspect Drug Dis Des 19:47CrossRefGoogle Scholar
  50. 50.
    Ertl P, Rohde B, Selzer P (2000) J Med Chem 43:3714CrossRefGoogle Scholar
  51. 51.
    Ghose AK, Crippen GM (1987) J Chem Inf Comput Sci 27:21CrossRefGoogle Scholar
  52. 52.
    Miller KJ (1990) J Am Chem Soc 112:8533CrossRefGoogle Scholar
  53. 53.
    Gasteiger J, Marsili M (1978) Tetrahedron Lett 19:3181CrossRefGoogle Scholar
  54. 54.
    Pauling L (1939) The nature of chemical bond. Cornell University Press, Ithaca, New YorkGoogle Scholar
  55. 55.
    Kier LB, Hall LH (1986) Molecular connectivity in structure–activity analysis. Research Studies Press, Letchworth, UKGoogle Scholar
  56. 56.
    Consonni V, Todeschini R, Pavan M (2002) J Chem Inf Comput Sci 42:682CrossRefGoogle Scholar
  57. 57.
    Todeschini R, Gramatica P (1998) Perspect Drug Dis Des 9–11:355CrossRefGoogle Scholar
  58. 58.
    Jacobson N (1985) In: Freeman WHC (ed) Basic algebra I. New York, pp 343–361Google Scholar
  59. 59.
    Riley KF, Hobson MP, Vence SJ (1998) Mathematical methods for physics and engineering. Cambridge University PressGoogle Scholar
  60. 60.
    Werner G (1981) Linear algebra, 4th edn Springer-Verlag, New YorkGoogle Scholar
  61. 61.
    Walker PD, Mezey PG (1993) J Am Chem Soc 115:12423CrossRefGoogle Scholar
  62. 62.
    Klein DJ (2003) Internet Electron J Mol Des 2:814Google Scholar
  63. 63.
    Negwer M (1987) Organic-chemical drugs and their synonyms. Akademie-Verlag, BerlinGoogle Scholar
  64. 64.
    STATISTICA (data analysis software system), v S I (2001) www.statsoft.comGoogle Scholar
  65. 65.
    Xu J, Hagler A (2002) Molecules 7:566CrossRefGoogle Scholar
  66. 66.
    Mc Farland JW, Gans DJ (1995) In: Waterbeemd H (ed), Chemometric Methods in Molecular Design. VCH Publishers, New York, pp 295–307Google Scholar
  67. 67.
    Johnson RA, Wichern DW (1988) Applied multivariate statistical analysis. Prentice-Hall, New JerseyGoogle Scholar
  68. 68.
    Duart MJ, Garcia-Domenech R, Anton-Fos GM, Galvez J (2001) J Comput Aided Mol Des 15:561CrossRefGoogle Scholar
  69. 69.
    van de Waterbeemd H (1995) In: van de Waterbeemd H (ed) Chemometric methods in molecular design. VCH Publishers, Weinheim, pp 265–288Google Scholar
  70. 70.
    de Julian-Ortiz JV, de Alapont CG, Ríos-Santamarina I, Garcia-Domenech R, Galvez E (1998) J Mol Graphics Mod 16:14CrossRefGoogle Scholar
  71. 71.
    Gálvez J, García R, Salabert MT, Soler R (1994) J Chem Inf Comput Sci 34:520CrossRefGoogle Scholar
  72. 72.
    Gonzales-Diaz H, Marrero Ponce Y, Hernadez I, Bastida I, Tenorio E, Nasco O, Uriarte E, Castanedo N, Cabrera MA, Aguila E, Marrero O, Morales A, Perez M (2003) Chem Res Toxicol 16:1318CrossRefGoogle Scholar
  73. 73.
    Estrada E, Peña A (2000) Bioorg Med Chem 8:2755CrossRefGoogle Scholar
  74. 74.
    Randić M (1991) J Mol Struct (Theochem) 233:45CrossRefGoogle Scholar
  75. 75.
    Randić M (1991) J Chem Inf Comput Sci 31:311CrossRefGoogle Scholar
  76. 76.
    Randić M (1991) New J Chem 15:517Google Scholar
  77. 77.
    Lučić B, Nikolić S, Trinajstić N, Jurić D (1995) J Chem Inf Comput Sci 35:532Google Scholar
  78. 78.
    Klein DJ, Randić M, Babić D, Lučić B, Nikolić S, Trinajstić N (1997) Int J Quantum Chem 63:215CrossRefGoogle Scholar
  79. 79.
    Estrada E, Uriarte E (2001) Curr Med Chem 8:1573Google Scholar
  80. 80.
    Khan KM, Maharvi GM, Khan MT, Jabbar Shaikh A, Perveen S, Begum S, Choudhary MI (2006) Bioorg Med Chem 14:344CrossRefGoogle Scholar
  81. 81.
    Hearing VJ (1987) Methods in enzymology. Academic Press, New YorkGoogle Scholar
  82. 82.
    Wold S, Erikson L (1995) In: van de Waterbeemd H (ed) Chemometric methods in molecular design. VCH Publishers, New York, pp 309–318Google Scholar
  83. 83.
    Golbraikh A, Tropsha A (2002) J Mol Graph Model 20:269CrossRefGoogle Scholar
  84. 84.
    Okombi S, Rival D, Bonnet S, Mariotte AM, Perrier E, Boumendjel A (2006) J Med Chem 49:329CrossRefGoogle Scholar
  85. 85.
    Zhang J-P, Chen Q-X, Song K-K, Xie J-J (2006) Food Chem 92:579CrossRefGoogle Scholar
  86. 86.
    Apweiler R (2003) Biosilico 1:5CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Yovani Marrero-Ponce
    • 1
    • 2
    • 3
  • Mahmud Tareq Hassan Khan
    • 4
    • 5
  • Gerardo M. Casañola-Martín
    • 2
    • 6
  • Arjumand Ather
    • 7
  • Mukhlis N. Sultankhodzhaev
    • 8
  • Ramón García-Domenech
    • 3
  • Francisco Torrens
    • 1
  • Richard Rotondo
    • 9
  1. 1.Institut Universitari de Ciència MolecularUniversitat de ValènciaValenciaSpain
  2. 2.Unit of Computer-Aided Molecular “Biosilico” Discovery and Bioinformatic Research (CAMD-BIR Unit), Faculty of Chemistry-Pharmacy, Department of Drug Design, Chemical Bioactive CenterCentral University of Las VillasSanta Clara, Villa ClaraCuba
  3. 3.Unidad de Investigación de Diseño de Fármacos y Conectividad Molecular, Departamento de Química Física, Facultad de FarmaciaUniversitat de ValènciaValenciaSpain
  4. 4.Pharmacology Research Lab., Faculty of Pharmaceutical SciencesUniversity of Science and TechnologyChittagongBangladesh
  5. 5.Department of Pharmacology, Institute of Medical BiologyUniversity of TromsoTromsoNorway
  6. 6.Department of Biological Sciences, Faculty of Agricultural SciencesUniversity of Ciego de AvilaCiego de AvilaCuba
  7. 7.The Norwegian Structural Biology Centre (NorStruct)University of TromsoTromsoNorway
  8. 8.S. Yunusov Institute of Chemistry of Plant SubstancesAcademy of SciencesUzbekistanTashkent
  9. 9.Advanced Medisyns, Inc.MinnetonkaUSA

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