Front Biosci (Schol Ed). 2025 Jun 25;17(2):38998. doi: 10.31083/FBS38998.ABSTRACTBACKGROUND: Histone deacetylase 1 (HDAC1) is a critical epigenetic regulator involved in chromatin remodeling and transcriptional repression, making it a valuable target for cancer therapy. Selective inhibition of HDAC1 represents a promising approach to cancer treatment, as it modulates gene expression and induces apoptosis in tumor cells.METHODS: Two novel hydroxamate-based HDAC1 inhibitors, compounds 4 and 6, were designed and evaluated using molecular docking, molecular dynamics (MD) simulations, and enzymatic inhibition assays. Molecular docking assessed binding interactions, while MD simulations evaluated the stability of the ligand-protein complexes. Enzymatic inhibition assays were used to determine the IC50 values and evaluate the potency of the compounds.RESULTS: Molecular docking revealed that both compounds exhibited significant interactions with HDAC1, including hydrophobic contacts, hydrogen bonding, and zinc coordination. Compound 4 demonstrated a stronger binding affinity (-6.2 kcal/mol) compared to compound 6 (-5.7 kcal/mol). The MD simulations confirmed that compound 4 exhibited greater stability, with divalent zinc coordination (4.3 Å and 4.8 Å), whereas compound 6 showed weaker monovalent coordination (4.4 Å). Enzymatic assays demonstrated that compound 4 had an IC50 of 2.96 ± 0.4 μM, while compound 6 exhibited an IC50 of 4.76 ± 0.5 μM; thus, compound 4 possesses superior inhibitory potency.CONCLUSIONS: Compound 4 exhibits enhanced binding affinity, stability, and enzymatic inhibition compared to compound 6, suggesting that this compound may serve as a promising lead for the development of selective HDAC1 inhibitors.PMID:40613210 | DOI:10.31083/FBS38998