Pharmacophore assessment through 3-D QSAR: evaluation of the predictive ability on new derivatives by the application on a series of antitubercular agents.

Laura Friggeri (1) , Flavio Ballante (2) , Rino Ragno (2) , Ira Musmuca (2) , Daniela de Vita (1) , Fabrizio Manetti (3) , Mariangela Biava (1) , Luigi Scipione (1) , Roberto Di Santo (1) , Roberta Costi (1) , Marta Feroci (4) , Silvano Tortorella (1)

1 Department of Medicinal Chemistry and Technologies
2 Rome Center for Molecular Design
3 UNISI - Università degli Studi di Siena = University of Siena
4 Dipartimento di Scienze di Base e Applicate per l'Ingegneria

Pharmacophoric mapping is a useful procedure to frame, especially when crystallographic receptor structures are unavailable as in ligand-based studies, the hypothetical site of interaction. In this study, 71 pyrrole derivatives active against M. tuberculosis were used to derive through a recent new 3-D QSAR protocol, 3-D QSAutogrid/R, several predictive 3-D QSAR models on compounds aligned by a previously reported pharmacophoric application. A final multiprobe (MP) 3-D QSAR model was then obtained configuring itself as a tool to derive pharmacophoric quantitative models. To stress the applicability of the described models, an external test set of unrelated and newly synthesized series of R-4-amino-3-isoxazolidinone derivatives found to be active at micromolar level against M. tuberculosis was used, and the predicted bioactivities were in good agreement with the experimental values. The 3-D QSAutogrid/R procedure proved to be able to correlate by a single multi-informative scenario the different activity molecular profiles thus confirming its usefulness in the rational drug design approach.

Domains: Pharmaceutical sciences

Laura Friggeri, Flavio Ballante, Rino Ragno, Ira Musmuca, Daniela de Vita, et al.. Pharmacophore assessment through 3-D QSAR: evaluation of the predictive ability on new derivatives by the application on a series of antitubercular agents.. Journal of Chemical Information and Modeling, 2013, 53 (6), pp.1463-74. ⟨10.1021/ci400132q⟩. ⟨pasteur-00968810⟩