Computational Study of Natural Therapeutic Alternatives against CBX4 Associated with the Development of Presbycusis

Presbycusis is a clinical condition related to hearing impairment caused by chronic noise exposure, senescence, or genes that exacerbate the loss of the inner ear. Polycomb Chromobox (CBX) proteins regulate gene expression by targeting the Polycomb repressor complex 1 (PRC1) to histone H3K27me3 sites via their chromodomains, playing a key role in developing presbycusis. This study aims to search for new agents to decrease the progression of the hearing damage pathway CBX4. Initially, a review that identified 17 molecules with reported activity in auditory conditions was done. Molecular dynamics (MD) simulation was performed for the native protein and principal systems employing AMBER20 software. Root mean square deviation (RMSD), RMSF (root mean square fluctuation), solvent accessible surface area (SASA), radius of gyration (RoG) analyses, free energy molecular mechanics generalized born surface area (MMGBSA), and principal components analysis (PCA) calculations were obtained. The main results are that oridonin and curcumin have shown binding energy for the CBX4 protein, with higher affinity than UNC3688. In MDs, the CBX4-oridinin complex showed a more stable profile regarding RMSD and SASA, while the CBX4-curcumin compound evidenced better conformational and energetic stability. In conclusion, oridonin and curcumin could be potential inhibitors for CBX4.