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New Antitrichomonal Drug-like Chemicals Selected by Bond (Edge)-Based TOMOCOMD-CARDD Descriptors

Unit of Computer-Aided Molecular "Biosilico" Discovery and Bioinformatic Research (CAMD-BIR Unit), Faculty of Chemistry-Pharmacy, Central University of Las Villas, Villa Clara, Cuba, Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain

Oscar M. Rivera-Borroto

Unit of Computer-Aided Molecular "Biosilico" Discovery and Bioinformatic Research (CAMD-BIR Unit), Faculty of Chemistry-Pharmacy, Central University of Las Villas, Villa Clara, Cuba, Bioinformatics Group, Informatics Research Center (CEI), Faculty of Mathematics, Physics and Computer Science, Central University of Las Villas, Villa Clara, Cuba

Yovani Marrero-Ponce

Unit of Computer-Aided Molecular "Biosilico" Discovery and Bioinformatic Research (CAMD-BIR Unit), Faculty of Chemistry-Pharmacy, Central University of Las Villas, Villa Clara, Cuba, Institut Universitari de Ciència Molecular, Universitat de València, Edifici d'Instituts de Paterna, València, Spain, ymarrero77{at}yahoo.es

Alina Montero

Unit of Computer-Aided Molecular "Biosilico" Discovery and Bioinformatic Research (CAMD-BIR Unit), Faculty of Chemistry-Pharmacy, Central University of Las Villas, Villa Clara, Cuba

Yanetsy Machado Tugores

Unit of Computer-Aided Molecular "Biosilico" Discovery and Bioinformatic Research (CAMD-BIR Unit), Faculty of Chemistry-Pharmacy, Central University of Las Villas, Villa Clara, Cuba

José Antonio Escario

Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain

Alicia Gómez Barrio

Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain

David Montero Pereira

Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain

Juan José Nogal

Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain

Vladimir V. Kouznetsov

Laboratorio de Química Orgánica y Biomolecular, Escuela de Química, Universidad Industrial de Santander, Bucaramanga, Colombia

Cristian Ochoa Puentes

Laboratorio de Química Orgánica y Biomolecular, Escuela de Química, Universidad Industrial de Santander, Bucaramanga, Colombia

Arnold R. Bohórquez

Laboratorio de Química Orgánica y Biomolecular, Escuela de Química, Universidad Industrial de Santander, Bucaramanga, Colombia

Ricardo Grau

Bioinformatics Group, Informatics Research Center (CEI), Faculty of Mathematics, Physics and Computer Science, Central University of Las Villas, Villa Clara, Cuba

Francisco Torrens

Institut Universitari de Ciència Molecular, Universitat de València, Edifici d'Instituts de Paterna, València, Spain

Froylán Ibarra-Velarde

Department of Parasitology, Faculty of Veterinarian Medicinal and Zootecnic, Universidad Nacional Autónoma de México, Mexico City, Mexico

Vicente J. Arán

Instituto de Química Médica, CSIC, Madrid, Spain

Bond-based quadratic indices, new TOMOCOMD-CARDD molecular descriptors, and linear discriminant analysis (LDA) were used to discover novel lead trichomonacidals. The obtained LDA-based quantitative structure-activity relationships (QSAR) models, using nonstochastic and stochastic indices, were able to classify correctly 87.91% (87.50%) and 89.01% (84.38%) of the chemicals in training (test) sets, respectively. They showed large Matthews correlation coefficients of 0.75 (0.71) and 0.78 (0.65) for the training (test) sets, correspondingly. Later, both models were applied to the virtual screening of 21 chemicals to find new lead antitrichomonal agents. Predictions agreed with experimental results to a great extent because a correct classification for both models of 95.24% (20 of 21) of the chemicals was obtained. Of the 21 compounds that were screened and synthesized, 2 molecules (chemicals G-1, UC-245) showed high to moderate cytocidal activity at the concentration of 10 µg/ml, another 2 compounds (G-0 and CRIS-148) showed high cytocidal activity only at the concentration of 100 µg/ml, and the remaining chemicals (from CRIS-105 to CRIS-153, except CRIS-148) were inactive at these assayed concentrations. Finally, the best candidate, G-1 (cytocidal activity of 100% at 10 µg/ml) was in vivo assayed in ovariectomized Wistar rats achieving promising results as a trichomonacidal drug-like compound. (Journal of Biomolecular Screening 2008:785-794).

Key Words: bond-based TOMOCOMD-CARDD quadratic indices • LDA-based QSAR model • virtual screening • lead generation • trichomonacidal • cytostatic and cytocidal activity

This version was published on September 1, 2008

Journal of Biomolecular Screening, Vol. 13, No. 8, 785-794 (2008)
DOI: 10.1177/1087057108323122


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