Conformational properties of amphotericin B amide derivatives--impact on selective toxicity.
Even though it is highly toxic, Amphotericin B (AmB), an amphipathic polyene macrolide antibiotic, is used in the treatment of severe systemic fungal infections as a life-saving drug. To examine the influence of conformational factors on selective toxicity of these compounds, we have investigated the conformational properties of five AmB amide derivatives. It was found that the extended conformation with torsional angles (phi,psi)=(290 degrees,180 degrees) is a common minimum of the potential energy surfaces (PES) of unsubstituted AmB and its amide derivatives. The extended conformation of the studied compounds allows for the formation of an intermolecular hydrogen bond network between adjacent antibiotic molecules in the open channel configuration. Therefore, the extended conformation is expected to be the dominant conformer in an open AmB (or its amide derivatives) membrane channel. The derivative compounds for calculations were chosen according to their selective toxicity compared to AmB and they had a wide range of selective toxicity. Except for two AmB derivatives, the PES maps of the derivatives reveal that the molecules can coexist in more than one conformer. Taking into account the cumulative conclusions drawn from the earlier MD simulation studies of AmB membrane channel, the results of the potential energy surface maps, and the physical considerations of the molecular structures, we hypothesize a new model of structure-selective toxicity of AmB derivatives. In this proposed model the presence of the extended conformation as the only well defined global conformer for AmB derivatives is taken as the indicator of their higher selective toxicity. This model successfully explains our results. To further test our model, we also investigated an AmB derivative whose selective toxicity has not been experimentally measured before. Our prediction for the selective toxicity of this compound can be tested in experiments to validate or invalidate the proposed model.
Resat
H
H
Koç University, School of Arts and Sciences, Istinye Istanbul, Turkey. haluk.resat@pnl.gov
Sungur
F A
FA
Baginski
M
M
Borowski
E
E
Aviyente
V
V
D000577:Amides / Q000737:chemistry; D000666:Amphotericin B / Q000737:chemistry* / Q000633:toxicity; D000935:Antifungal Agents / Q000737:chemistry* / Q000633:toxicity; D008968:Molecular Conformation
D000577:Amides; D000935:Antifungal Agents; D000666:Amphotericin B