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

Research paper by Ugo U Cosentino, M Rosaria MR Varí, A A Gloria AA Saracino, Demetrio D Pitea, Giorgio G Moro, Mario M Salmona

Indexed on: 14 Dec '04Published on: 14 Dec '04Published in: Journal of Molecular Modeling



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.