Conformational properties of amphotericin B amide derivatives - impact on selective toxicity

Even though it is highly toxic, Amphotericin B (AmB), an amphipathic polyen e macrolide antibiotic, is used in the treatment of severe systemic fungal infections as a life-saving drug. To examine the influence of conformationa l factors on selective toxicity of these compounds, we have investigated th e conformational properties of five AmB amide derivatives. It was found tha t the extended conformation with torsional angles (phi,psi)=(290 degrees,18 0 degrees ) is a common minimum of the potential energy surfaces (PES) of u nsubstituted AmB and its amide derivatives. The extended conformation of th e studied compounds allows for the formation of an intermolecular hydrogen bond network between adjacent antibiotic molecules in the open channel conf iguration. Therefore, the extended conformation is expected to be the domin ant conformer in an open AmB (or its amide derivatives) membrane channel. T he derivative compounds for calculations were chosen according to their sel ective toxicity compared to AmB and they had a wide range of selective toxi city. Except for two AmB derivatives, the PES maps of the derivatives revea l that the molecules can coexist in more than one conformer. Taking into ac count the cumulative conclusions drawn from the earlier MD simulation studi es of AmB membrane channel, the results of the potential energy surface map s, and the physical considerations of the molecular structures, we hypothes ize 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 t heir higher selective toxicity. This model successfully explains our result s. To further test our model, we also investigated an AmB derivative whose selective toxicity has not been experimentally measured before. Our predict ion for the selective toxicity of this compound can be tested in experiment s to validate or invalidate the proposed model.