Structural insights for aminoglycoside induced nephrotoxicity: Molecular modeling studies of the calreticulin‐gentamicin complex

Gentamicin, an aminoglycoside, is used for the treatment of gram negative infections. The side effect is the nephrotoxicity resulting from its binding to chaperones. We provide a detailed structural insight of the complex of calreticulin with gentamicin by molecular modeling. The docking studies are done using LigandFit docking protocol available in in‐house Discovery Studio 2.0. The gentamycin binds to the lectin site of the calreticulin and lies in the concave channel formed by the β sheets. It makes hydrogen bonds with G124, Y128 and makes van der Waals contacts with K111, D135, W319, all of which are important functional residues. Further, it also interacts with the disulfide bond between C105 and C137 which are crucial for the chaperonic function. The superimposition of the modeled complex with the only available crystal structure complex of calreticulin with a tetrasaccharide shows the rings of the drug occupying the positions of three of the sugar molecules. The oxygen atoms of the glycosidic linkage of these two ligands have a positional deviation of 0.5. The predicted binding constant of 42.7μM is in accordance with the previous kinetic studies. The details therefore strongly suggest gentamycin as a competitive inhibitor with calreticulin as the secondary drug target. This helps to understand the structural basis for the nephrotoxicity caused by gentamycin. The fellowship from CSIR to GH is acknowledged.