A battleship between hydroxamates versus non-hydroxamates: Exploring semi-empirical quantum properties, chemical space network, activity landscape, scaffold diversity of HDAC3 inhibitors to improve memory and learning

Memory and learning are fundamental brain processes, with Histone Deacetylases (HDACs), particularly Histone Deacetylase 3 (HDAC3), playing a crucial role in long-term memory. HDAC3 inhibitors (HDAC3i) have been shown to enhance memory function, making the identification of potential HDAC3i candidates valuable for memory-related disorders. In this study, we investigate the variability of semi-empirical quantum chemical parameters related to zinc binding patterns in a large set of hydroxamate and non-hydroxamate HDAC3i. We analyze the chemical space and structure-activity relationships (SAR) of these compounds, employing molecular clustering and visualization techniques. An analysis of the electronic properties of two representative inhibitors is also presented through density functional theory (DFT) calculations. The results indicate that non-hydroxamate HDAC3i exhibit lower formation energies than hydroxamates but are generally lower effective inhibitors, suggesting that inhibition depends on binding site stabilization and specific molecular interactions. The study also reveals that effective inhibition arises from global molecular stabilization and contributions from specific motifs, such as the Cap and linker regions. Our clustering analysis identifies distinct structural motifs, with hydroxamates showing greater chemical uniformity while non-hydroxamates display higher scaffold diversity. These findings provide a framework for optimizing lead compounds in developing HDAC3 inhibitors, offering insights into their potential therapeutic applications in memory disorders and HDAC3-related conditions.