Summary
In this work, the TOMOCOMD-CARDD approach has been applied to estimate the anthelmintic activity. Total and local (both atom and atom-type) quadratic indices and linear discriminant analysis were used to obtain a quantitative model that discriminates between anthelmintic and non-anthelmintic drug-like compounds. The obtained model correctly classified 90.37% of compounds in the training set. External validation processes to assess the robustness and predictive power of the obtained model were carried out. The QSAR model correctly classified 88.18% of compounds in this external prediction set. A second model was performed to outline some conclusions about the possible modes of action of anthelmintic drugs. This model permits the correct classification of 94.52% of compounds in the training set, and 80.00% of good global classification in the external prediction set. After that, the developed model was used in virtual in silicoscreening and several compounds from the Merck Index, Negwer‘s handbook and Goodman and Gilman were identified by models as anthelmintic. Finally, the experimental assay of one organic chemical (<b>G-1</b>) by an in vivo test coincides fairly well (100) with model predictions. These results suggest that the proposed method will be a good tool for studying the biological properties of drug candidates during the early state of the drug-development process.
Similar content being viewed by others
References
P. Kohler (2001) Int. J. Parasitol. 31 336
R.J. Martin A.P. Robertson H. Bjorn (1997) Parasitology 114 S111
R.K. Pichard (1994) Vet. Parasitol. 54 259
R.J. Martin (1997) Vet. J. 154 11
H. González Díaz E. Olazábal N. Castañedo I. Hernández A. Morales H.S. Serrano J. González R. Ramos (2002) J. Mol. Mod. 8 237
D. Cioli (1998) Parasitol. Today 14 418
M.J. Conceicao C.A. Argento A. Correa (2000) Memorias instituto Oswaldo Cruz 95 375
Y.S. Liang G.C. Coles M. Doenhoff (2000) J. Trop. Med. Int. Health 5 72
J.A. Reynoldson J.M. Behnke L.J. Pallant M.G. Macnish F. Gilbert S. Giles R.J. Spargo R.C. Thompson (1997) Acta Trop. 68 301
N.C. Sangster J. Gill (1999) Parasitol. Today 15 141
C.C. Coles (1999) J. Med. Microbiol. 48 323
L. Moll C.P. Gaasenbeek P. Vellena F.H. Borgsteede (2000) Vet. Parasitol. 91 153
J. Rothwell N. Sangster (1997) Int. J. Parasitol. 27 313
A.M. Evans R.J. Martin (1996) Br. J. Pharmacol. 118 1127
R.J. Martin (1993) Pharmacol. Therapeut 58 13
S.J. Robertson R.J. Martin (1993) Br. J. Pharmacol. 108 170
R.J. Martin (1985) Br. J. Pharmacol. 84 445
Martin, R.J., Parasitology, 147 (1996).
D.F. Cully H. Wilkinson D.K. Vassilitis A. Etter J.P. Arena (1996) Parasitology 113 191
C.A. Redman A.P. Robertson P.G. Fallon J. Modha J.R. Kusel M.J. Doenhoff R.J. Martin (1996) Parasitol. Today 12 14
M.H. Roos M.S.G. Kwa W.M. Grant (1995) Parasitol. Today 11 148
Q.A. McKellar L.D.B. Kinabo (1991) Br. Vet. J. 147 306
S.R. Edwards A.J. Campbell M. Sheers R.J. Moore P.E. Montague (1981) Mol. Biochem. Parasitol. 2 339
S.R. Edwards A.J. Campbell M. Sheers R.J. Moore P.E. Montague (1981) Mol. Biochem. Parasitol. 2 323
M.D. Schulman D.A. Ostlind D. Valentino (1982) Mol. Biochem. Parasitol. 5 133
R.M. Maizels D.A. Denham (1992) Parasitology 105 49
E. Estrada (2000) Environ. Res. 11 55
E. Estrada A. Peña (2000) Bioorg. Med. Chem. 8 2755
Marrero-Ponce, Y. and Romero, V., TOMOCOMD software, version 1.0, 2002, Central University of Las Villas. TOMOCOMD (TOpological MOlecular COMputer Design) for Windows, version 1.0 is a preliminary experimental version; in the future a professional version can be obtained upon request from Y. Marrero: yovanimp @qf.uclv.edu.cu or ymarrero77@yahoo.es.
Y. Marrero-Ponce (2003) Molecules 8 687
Y. Marrero-Ponce M.A. Cabrera V. Romero E. Ofori L.A. Montero (2003) ArticleTitleInt J. Mol. Sci. 4 512
Y. Marrero-Ponce M.A. Cabrera V. Romero D.H. González F. Torrens (2004) J. Pharm. Pharm. Sci. 7 186
Marrero-Ponce, Y., Nodarse, D., González-Díaz, H., Ramos, R., Romero-Zaldivar, V., Torrens, F. and Castro, E. Nucleic Acid Quadratic Indices of the “Macromolecular Graph’s Nucleotides Adjacency Matrix”. Modeling of Footprints after the Interaction of Paromomycin with the HIV-1 ψ-RNA Packaging Region. CPS: physchem/0401004.
L.H. Hall L.B. Kier (1995) J. Chem. Inf. Comput. Sci. 35 1039
Cotton, F.A., Adv. Inorg. Chem. Revolucionaria Havana, 1966.
M. Negwer (1987) Organic-chemical Drugs and their synonyms Akademie-Verlag Berlin
The Merck Index, Twelfth Edition. Chapman & Hall, New York, 1996.
STATISTICA ver. 5.5, Statsoft, Inc., 1999.
H. González-Díaz Y. Marrero-Ponce I. Hernández I. Bastida E. Tenorio O. Nasco E. Uriarte N. Castañedo M.A. Cabrera E. Aguila O. Marrero A. Morales M. Pérez (2003) Chem. Res. Toxicol. 16 1318
E. Estrada A. Peña R. Garcia-Domenech (1998) J. Comput.-Aided Mol. Des. 12 583
J.V. Julian-Ortiz J. Gálvez C. Muños-Collado R. García-Domenech C. Gimeno-Cardona (1999) J.␣Med. Chem. 42 3308
F.J. Milligen J.B. Cornelissen C.P. Guasenbeek B.A. Bokhout (1998) J. Immunol. Met. 213 183
J. Mitterpak M. Mendéz M. Mauri (1972) Serie biológica 30 1
E. Olazábal A. Morales H. Serrano E. Brito (1999) Vet. Méx. 30 109
C. Ping A. Hayes (1994) Acute toxicity and eyes irritancy: Principles and Methods of Toxicology EditionNumber3 Raven Press Ltd New York
J. Corba S. Velebny R. Spaldonova (1981) Helminthology 18 43
J.S. Steward (1955) Parasitology 45 231
I.B. Wood N.K. Amaral K. Bairden J. Duncan T. Kassai J.B. Malone J.A. Pankavich R.K. Reinecke O. Slocombe S.M. Taylor J. Vercruysse (1995) Vet. Parasitol. 58 181
N. Tsocheva L. Krustev O. Polyakova (1992) Helminthology 27 261
I. Poitou E. Baeza C. Boulard (1992) Vet Parasitol. 45 59
Espaine, L., Lines, R. and Demedio, J., Manual de Parasitología y enfermedades Parasitarias I. Editorial MES, Habana (1996) 103.
A. Golbraikh A. Tropsha (2002) J. Mol. Graphic Model. 20 269
C. Watson (2003) Biosilico 3 83
Lajiness, M.S., In Rouvray, D.H. (Ed.), Computational Chemical Graph Theory, Nova Science, New York, 1990, pp. 299.
W.P. Walters M.T. Stahl M.A. Murcko (1998) Drug Discov. Today 3 160
Conder, G., Kuo, M., Marshall, V. and Zielinski, R., United States Patent 5,643,940 (1997).
Flynn, A., United States Patent 4,303,666 (1981).
Meek, W., United States Patent 3,949,075 (1976).
Scherkenbeck, J., European Patent 0 664 297, A1 (1988).
Serban, A., Watson, K., Wilshire, C. and Forsyth, B., United States Patent 4,460,588 (1984).
N. Walchshofer I. Delabre-Defayolle J. Paris A.F. Petavy (1990) J. Pharm. Sci. 7 79
R.A. Ames (1991) J. Pharm. Sci. 3 293
J.R. Ames N. Castognoli M.D. Ryan P. Kavacic (1986) Free Rad. Res. Commun. 2 107
N.F.H. Ho S.M. Sims T.J. Vidmar J.S. Day C.L. Barsuhn E.M. Thomas T.G. Geary D. Thompson (1994) J. Pharm. Sci. 83 1052
Goodman, A.G., Goodman, L.S. and Gilman, A., Las bases Farmacológicas de la Terapeutica, 9na Ed. Vol II, McGraw-Hill, New York, 1996.
B. Alberts D. Bray J. Lewis M. Raff K. Roberts J.D. Watson (1994) Molecular Biology of the Cell EditionNumber3 Garland Publishing, Inc. New York and London
J.M. Blondeau N. Castañedo O. Gonzalez R. Medina E. Silveira (1999) Antimicrob. Agents Chemother. 11 1663
M.A. Cabrera H. González E. Jiménez D.O. Pérez E. Gómez N. Castañedo (2001) Eur. Bull. Drug Res. 9 1
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Marrero-Ponce, Y., Castillo-Garit, J.A., Olazabal, E. et al. Tomocomd-Cardd, a novel approach for computer-aided ‘ rational’ drug design: I. Theoretical and experimental assessment of a promising method for computational screening and in silico design of new anthelmintic compounds. J Comput Aided Mol Des 18, 615–634 (2004). https://doi.org/10.1007/s10822-004-5171-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10822-004-5171-y