Molecular modeling of amphotericin B–ergosterol primary complex in water II

Abstract

The work presented is a part of our continual study on the behavior of the polyene macrolide antibiotic amphotericin B (AmB) complexes with sterols on the molecular level. In contrast to the previously researched AmB-ergosterol binary complex, the AmB-ergosterol-AmB aggregates simulated of 2:1 stoichiometry retain significantly higher stability and relatively rigid, "sandwich" geometry. Van der Waals forces with a considerable share of the electrostatic interactions are responsible for such behavior. System of the intermolecular hydrogen bonds also seems to be of notable importance for the complex's structure preservation. The most energetically favored geometries match fairly close the geometric criteria and the network of interactions postulated in the contemporary hypothetical and computational models of antibiotic-sterol complexes. On the basis of works previously published and the present study novel hypotheses on the AmB selectivity towards sterols varying in chemical structure and on the possible mechanisms of channel structure formation were presented.A

Comparative molecular modelling of biologically active sterols

“…Other factors should be taken into account when discussing the phenomenon of AmB -sterol differential affinity in the complex formation. The reported results of simulations of isolated sterol molecules confirm our findings from simulations of AmBsterol complexes [19,20]. Molecules of ergosterol or cholesterol (unpublished results) and antibiotic may fit their shapes to each other to some extent in order to assure the largest intermolecular contact.…”

“…It should be noted that during our simulations all the sterols studied existed predominantly in the conformation Àsc/ap. According to the present model of the AmB-sterol complex and our previous studies [19,20], also other conformations, in which the side chain is coplanar to the ring system (+sc/Àsc and Àsc/Àsc), could form a stable complex. Thus, for all the sterols studied conformations that are able to form the complex have been observed during more than 57% of the simulation time.…”

“…During review of temporary snapshots of the complexes we did not notice any steric obstacles preventing interaction between cholesterol and AmB suggested by our colleagues. Possible model of antibiotic -sterol interactions was discussed in our last paper on AmB -ergosterol complexes with 2:1 stoichiometry [20].…”

Antifungal activity of synthetic naphthoquinones against dermatophytes and opportunistic fungi: preliminary mechanism-of-action tests

“…The results showed that the MIC of IVS320 against C. albicans ATCC 36232 did not change in the presence of different concentrations (200 to 800 μg/mL) of exogenous ergosterol (Figure 2), suggesting that IVS320 does not act by interacting with ergosterol. In contrast, there was a 4× MIC increase with amphotericin B, which is known to have a strong affinity for ergosterol and served as the positive control in this assay [14]. …”

Anti-Candida albicanseffectiveness of citral and investigation of mode of action

“…In the presence of cholesterol, the MIC value of citral increased to 1024 µg/mL (two-fold), and the MIC of amphotericin B increased four times, as shown in Tables 3 and 4. Amphotericin B has a strong affinity for ergosterol, while it has a weak affinity for cholesterol, and this is due to the double bond in the ergosterol molecule increasing the stability of interaction between amphotericin B and ergosterol (Baran et al, 2009).…”