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

J Chem Inf Model. 2013 Jun 24;53(6):1463-74. doi: 10.1021/ci400132q. Epub 2013 May 17.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / chemistry*
  • Antitubercular Agents / pharmacology*
  • Drug Design
  • Humans
  • Models, Molecular
  • Mycobacterium tuberculosis / drug effects*
  • Oxazolidinones / chemistry
  • Oxazolidinones / pharmacology
  • Pyrroles / chemistry*
  • Pyrroles / pharmacology*
  • Quantitative Structure-Activity Relationship*
  • Tuberculosis / drug therapy

Substances

  • Antitubercular Agents
  • Oxazolidinones
  • Pyrroles