CONFORMATIONAL-ANALYSIS OF AMPHOTERICIN-B

Within a theoretical approach to the problem of antifungal action of A mphotericin B (AmB), a conformational analysis of the neutral and zwit terionic form of this antibiotic in vacuo was performed by the MM2P an d 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 impo rtant for the antifungal action of the drug. As a result of the MM2P c alculations, 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) we re previously observed experimentally for isolated molecules. Our othe r calculated conformers were not observed experimentally but we propos e that they may also appear in the AmB channel structure. The results of our conformational analysis were compared with experimental NMR dat a (nuclear Overhauser effects between selected hydrogen atoms) obtaine d previously [1]. New structural information obtained for AmB in the p resent work will be useful for building a molecular model of AmB-targe t interactions as well as for designing new derivatives of AmB. (C) 19 97 Elsevier Science B.V.