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Journal of Biomolecular Screening
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Search of Chemical Scaffolds for Novel Antituberculosis Agents

Angeles García-García

Jorge Gálvez

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

Jesus Vicente de Julián-Ortiz

Red de Investigación de Centros de Enfermedades Tropicales, Facultad de Farmacia, Universitat de València, Spain

Ramón García-Domenech

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

Carlos Muñoz

Departamento de Microbiología, Facultad de Medicina y Odontología, Universitat de València, Spain

Remedios Guna

Unidad de Investigación de Diseño de Fármacos y Conectividad Molecular, Departamento de Química Física, Facultad de Farmacia, Universitat de València, Spain; Departamento de Microbiología, Facultad de Medicina y Odontología, Universitat de València, Spain

Rafael Borrás

Departamento de Microbiología, Facultad de Medicina y Odontología, Universitat de València, Spain

A method to identify chemical scaffolds potentially active against Mycobacterium tuberculosis is presented. The molecular features of a set of structurally heterogeneous antituberculosis drugs were coded by means of structural invariants. Three techniques were used to obtain equations able to model the antituberculosis activity: linear discriminant analysis, multilinear regression, and shrinkage estimation–ridge regression. The model obtained was statistically validated through leave-n-out test, and an external set and was applied to a database for the search of new active agents. The selected compounds were assayed in vitro, and among those identified as active stand reserpine, N,N,N',N'-tetrakis-(2-pyridylmethyl)-ethylenediamine (TPEN), trifluoperazine, pentamidine, and 2-methyl-4,6-dinitro-phenol (DNOC). They show activity comparable to or superior to ethambutol, used in combination with other drugs for the prevention and treatment of Mycobacterium avium complex and drug-resistant tuberculosis.

Key Words: antituberculosis agents • topological indices • linear discriminant analysis • multilinear regression analysis • ridge regression • shrinkage regression • virtual screening • virtual combinatorial libraries

Journal of Biomolecular Screening, Vol. 10, No. 3, 206-214 (2005)
DOI: 10.1177/1087057104273486
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