Tetracycline and its analogues as inhibitors of amyloid fibrils: Searching for a geometrical pharmacophore by theoretical investigation of their conformational behavior in aqueous solution

Ugo Cosentino, M. Rosaria Varí, A. A Gloria Saracino, Demetrio Pitea, Giorgio Moro, Mario Salmona

Research output: Contribution to journalArticlepeer-review

Abstract

Tetracycline (TC) and its derivatives have recently been proposed as a new class of antagonists in prion diseases as they prevent the aggregation of prion protein peptides and their acquisition of protease resistance in vitro and in vivo. Looking for relationships between conformational flexibility and biological activity, we searched for a geometrical pharmacophore by investigating, in aqueous solution, the conformational behavior of 15 TCs in both the zwitterionic and the anionic forms. For TC similar conformational flexibility was found for the two forms and two main conformational families were detected, an extended and a folded conformation characterized by different intramolecular hydrogen-bond networks. On comparing the Molecular Mechanics results with the ab initio ones and the experimental evidence, it can be seen that the conformational behavior of TC is reasonably well predicted by the MM2 force field, whereas the conformational energies provided by the Amber force field are unreliable. The conformational analysis of the other TC derivatives was then performed by the MM2 force field. As a result, their conformational behavior was similar to that observed for TC itself. Despite the hydronaphthacene moiety's conformational flexibility, no geometrical pharmacophore was found among the TCs, i.e. properties other than geometrical ones should play a crucial role in determining their anti-fibrillogenic ability.

Original languageEnglish
Pages (from-to)17-25
Number of pages9
JournalJournal of Molecular Modeling
Volume11
Issue number1
DOIs
Publication statusPublished - Feb 2005

Keywords

  • Anti-amyloidogenic activity
  • Conformational analysis
  • Continuum solvation models
  • Geometrical pharmacophore
  • Tetracycline derivatives

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Biophysics
  • Computer Science Applications
  • Computational Theory and Mathematics

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