Conformational analysis of Amphotericin B

Within a theoretical approach to the problem of antifungal action of Amphotericin B (AmB), a conformational analysis of the neutral and zwitterionic form of this antibiotic in vacuo was performed by the MM2P and AMl methods. The analysis was carried out with regard to the mutual orientation of the macrolidic and glycosidic fragments of the molecule, which is defined by the phi and psi steric angles. This orientation defines the overall shape of the molecule and is postulated to be important for the antifungal action of the drug. As a result of the MM2P calculations, phi, psi steric energy and population maps were prepared. Several conformers were found on these maps but only two of them (one each for the zwitterionic and the neutral forms of the antibiotic) were previously observed experimentally for isolated molecules. Our other calculated conformers were not observed experimentally but we propose that they may also appear in the AmB channel structure. The results of our conformational analysis were compared with experimental NMR data (nuclear Overhauser effects between selected hydrogen atoms) obtained previously [1]. New structural information obtained for AmB in the present work will be useful for building a molecular model of AmB-target interactions as well as for designing new derivatives of AmB. (C) 1997 Elsevier Science B.V.