title: Pharmacophore assessment through 3-D QSAR: evaluation of the predictive ability on new derivatives by the application on a series of antitubercular agents.
abstract: 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.
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, P. le A. Moro 5, 00185 Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Friggeri
authors.forename: Flavio
authors.initials: F
authors.lastname: Ballante
authors.forename: Rino
authors.initials: R
authors.lastname: Ragno
authors.forename: Ira
authors.initials: I
authors.lastname: Musmuca
authors.forename: Daniela
authors.initials: D
authors.lastname: De Vita
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Manetti
authors.forename: Mariangela
authors.initials: M
authors.lastname: Biava
authors.forename: Luigi
authors.initials: L
authors.lastname: Scipione
authors.forename: Roberto
authors.initials: R
authors.lastname: Di Santo
authors.forename: Roberta
authors.initials: R
authors.lastname: Costi
authors.forename: Marta
authors.initials: M
authors.lastname: Feroci
authors.forename: Silvano
authors.initials: S
authors.lastname: Tortorella
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D023303:Oxazolidinones / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy
chemical_list: D000995:Antitubercular Agents; D023303:Oxazolidinones; D011758:Pyrroles