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Accessibility of aminoglycosides, isolated and in interaction with phosphatidylinositol, to water. A conformational analysis using the concept of molecular hydrophobicity potential

par Tulkens, Paul M.;Mingeot-Leclercq, Marie-Paule;Brasseur, Robert
Référence Biochemical pharmacology, 44, 10, page (1967-1975)
Publication Publié, 1992-11

Article révisé par les pairs

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Résumé :

The mode of interaction between aminoglycosides and negatively charged phospholipids plays a critical role in the inhibition of lysosomal phospholipases induced by these antibiotics and therefore in their nephrotoxicity. Previous works suggested that accessibility of the drug interacting with phospholipids to water could be crucial in this respect. We have used the concept of molecular hydrophobicity potential described by Brasseur [J Med Chem 266: 16120-16127, 1991] to visualize the hydrophobic and hydrophilic envelopes around aminoglycosides assembled with phosphatidylinositol molecules, and to obtain a three-dimensional representation of the complex formed. Using a series of different aminoglycosides, we showed that molecules with a lower inhibitory potential (gentamicin B, amikacin and isepamicin) are surrounded by both hydrophobic and hydrophilic envelopes whereas aminoglycosides which are more inhibitory are enveloped primarily by either hydrophilic (kanamycin A or B) or hydrophobic (gentamicin C1a) envelopes. This approach, which is here for the first time applied to the study of drug-lipid complexes, could help in the better understanding of the molecular mechanism of lysosomal phospholipase inhibition induced by aminoglycosides. © 1992.