Molecular Interactions of Kasugamycin with ALS-Associated Neuroinflammatory Proteins: An Integrated in Silico Investigation

Abstract

Amyotrophic lateral sclerosis (ALS) is associated with complex neuroimmune and inflammatory dysregulations where there is still room for new molecular targets and compounds of interest. Although Kasugamycin is an aminoglycoside antibiotic with several biological functions beyond its use as an antimicrobial drug, its interaction with proteins involved in ALS pathogenesis has not yet been adequately addressed. In this research, we used an integrated computational approach to investigate the possible interaction of kasugamycin with RAGE (AGER), Toll-like receptor 4 (TLR4), chitinase-3-like protein 1 (CHI3L1), and IL-13-related protein via molecular docking, followed by molecular dynamics (MD) simulation of the RAGE-kasugamycin complex. The docking analysis yielded binding energies of −7.75, −5.29, −4.01, and −3.75 kcal/mol for RAGE, CHI3L1, TLR4, and the IL-13-related protein, respectively. RAGE was the most promising interaction in the present computational study. Therefore, the RAGE-kasugamycin complex underwent a 100 ns MD simulation to evaluate its conformational stability and interaction capability. This information provides the rationale for considering the role of RAGE in future experiments on kasugamycin in neuroinflammatory diseases associated with ALS. However, it should be pointed out that the results have not shown any evidence of binding or target modulation, efficacy against inflammation, neuroprotection, and therapeutical effects. Overall, the study suggests that RAGE is a potential target for kasugamycin. Additionally, the comparative analysis of targets revealed that the interaction depends on specific targets.