The prolonged use of aminoglycoside antibiotics such as gentamicin and kanamycin to treat severe infections has been reported to cause side effects like irreversible hearing loss and kidney failure, which has led to the search for new therapies to prevent these adverse effects. One example is the use of flutamide, as it has exhibited cytoprotective properties against these antibiotics. The aim of this study is the computational analysis of the interaction of flutamide as a cytoprotective agent in the presence of these antibiotics when they bind to megalin, the protein responsible for their internalization. The interaction of flutamide with megalin in the presence of aminoglycosides revealed a potential mechanism responsible for the cytoprotective mechanism against these antibiotics.

Background. Gout is an inflammatory disease caused by the deposition of monosodium urate (MSU) crystals, leading to reactive oxygen species (ROS) production and activation of the NLRP3 inflammasome with subsequent IL-1β release. Poly-gallic acid (PGAL), enzymatically synthesized polymer, has demonstrated antioxidant and anti-inflammatory properties; however, its effect on MSU-induced inflammasome activation remains unclear. Thus, this work aims to evaluate the effect of PGAL on oxidative stress and inflammatory responses induced by MSU crystals in THP-1-derived macrophages. Methods. Macrophages were pretreated with PGAL and stimulated with MSU crystals. Cell viability, apoptosis, phagocytosis, ROS and NO production, soluble urate levels, and NLRP3 and IL-1β expression were evaluated. Molecular docking and binding free energy calculations were performed to characterize PGAL–MSU interactions. Results. PGAL significantly reduced ROS and NO production, and apoptosis. PGAL treatment also decreased MSU crystal phagocytosis and significantly reduced NLRP3 and IL-1β. Computational analysis revealed that PGAL interacts with MSU crystals predominantly through electrostatic interactions, including Na⁺ coordination and hydrogen bonding. Conclusions. PGAL attenuates MSU-induced oxidative stress and NLRP3/IL-1β activation, possibly by interfering with crystal internalization. These findings suggest a mechanism based on modulation of crystal–cell interactions and downstream inflammation responses.

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 10^th 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 (ΔG_b). 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 10^th 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 .

Obesity represents a global health problem; therefore, the search for new therapeutic agents is crucial. In this study, the molecular docking between the β₃-adrenergic receptor and cucurbitacin B (CuB) was investigated as a potential modulator of lipid metabolism. Through molecular coupling studies, the free binding energy (ΔGb) of CuB to the β₃-adrenergic receptor, a key regulator of lipid metabolism, was evaluated. The results demonstrated that the CuB binds favorably to the receptor. This interaction is mainly mediated by non-electrostatic interactions, rather than Coulombic forces. These findings suggest that CuB could modulate the activity of the β₃-adrenergic receptor, promoting lipolysis and representing a promising mechanism for the treatment of obesity.