<span style="mso-fareast-font-family: 'Palatino Linotype'; color: windowtext;">Megalin-Aminoglycosides Interaction as a Mechanism of Ototoxicity: Insights from <i>In Silico</i> Modeling and Cell Functionality Assays
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Background/Objectives: Aminoglycosides (AG) have been extensively used to treat bacterial diseases for decades. Nevertheless, despite their effectiveness, several secondary adverse effects (auditory, renal, and neurological) have been evident. Although the mechanisms of these side effects of AG are still unclear, there is a consensus that megalin is a drug receptor that participates in AG endocytosis. We aimed to explore the interaction between megalin and AGs to explain their ototoxicity side effect by combining in silico studies and cell functionality assays. Methods: Molecular dynamics simulations on the 10th CR domain of human megalin were performed using GROMACS. Seven commonly prescribed AG were docked against the surface of three conformations of this domain megalin derived from the simulations' trajectories. Gentamicin, the AG with the strongest affinity, was selected for cell functionality evaluation using HEK293 cells and Resazurin assays. Results: Docking results revealed that aspartic acids play a crucial role in the binding affinity to AGs, forming key electrostatic interactions. The models of the Megalin-AG complexes allowed the determination of electrostatic and non-electrostatic contributions to the free energy change of binding (ΔGb). Gentamicin, Tobramycin, and Neomycin showed a higher affinity for megalin than Kanamycin, Hygromycin, Paromomycin, and Streptomycin. Cell functionality of HEK293 cells was reduced by Gentamicin. Conclusion: the 10th CR domain of Megalin plays a critical role in AG-induced ototoxicity through electrostatic interactions mainly involving aspartic acid residues. It binds with higher affinity to Gentamicin, Tobramycin, and Neomycin than Kanamycin, Hygromycin, Paromomycin, and Streptomycin. Furthermore, we observed the reduced functionality of HEK293 cells induced by gentamicin. These results highlight megalin as a potential therapeutic target to mitigate/alleviate the adverse side effects of aminoglycoside.