Zinc Affinity of Benzamide-Based Histone Deacetylase Inhibitors: A DFT Study

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Epigenetics

Background:

• Histone deacetylase inhibitors (HDACi) are epigenetic anticancer drugs targeting Zn²⁺ in HDAC active sites.
• Benzamide-based HDACi (BBHDACi) offer improved isoform selectivity over hydroxamic acid-based inhibitors.
• Clinically relevant BBHDACi include Chidamide, Entinostat, Mocetinostat, Zabadinostat, and Tacedinaline.

Purpose of the Study:

• To investigate the intrinsic Zn²⁺ affinity and coordination behavior of various benzamide-based HDAC inhibitors.
• To compare the contribution of the conserved o-aminoanilide zinc-binding group (ZBG) versus linker and cap regions to metal binding.

Main Methods:

• Density Functional Theory (DFT) calculations at the B3LYP/6-311++g(d,p) level of theory.
• Inclusion of PCM solvation models for methanol (ε = 33) and water (ε = 78).
• Geometry optimization and coordination studies to analyze complex stability and binding energies.

Main Results:

• The trans (E) isomer of Chidamide was found to be thermodynamically preferred.
• BBHDACi preferentially form stable tetracoordinated Zn²⁺ complexes in polar media.
• Calculated substitution free energies indicated nearly identical intrinsic Zn²⁺ affinities (< ± 2 kcal.mol^-1) across the series.

Conclusions:

• The conserved o-aminoanilide ZBG contributes similarly to Zn²⁺ coordination in all studied BBHDACi.
• The overall binding affinity of BBHDACi is predominantly influenced by interactions involving the linker and cap regions.
• These findings highlight the importance of non-ZBG structural elements in modulating the efficacy of benzamide-based HDAC inhibitors.