In silico design of novel benzohydroxamate-based compounds as inhibitors of histone deacetylase 6 based on 3D-QSAR, molecular docking, and molecular dynamics simulations

Abstract

Histone deacetylase 6 (HDAC6) can deacetylate many substrates, including α-tubulin, cortactin, and HSP90α. This makes HDAC6 an interesting, emerging target. In this study, we selected 52 benzohydroxamate-based compounds and conducted 3D-QSAR studies using CoMFA and CoMSIA models. The results showed that CoMFA (n = 9; q² = 0.556; r² = 0.998) and CoMSIA (n = 9; q² = 0.656; r² = 0.996) have robust stability and predictability. The contour maps of the steric field, hydrophobic field, and hydrogen-bond donor field revealed the modified regions of these compounds. Subsequently, molecular docking was used to explore the docking mode of compounds and receptors. Based on these results, we designed 11 new benzohydroxamate-based compounds and predicted their activity and ADME/T properties. The results indicated that these compounds have strong pharmaceutical properties, and MD simulation analysis confirmed that Asp742 and His610 in the active site played a key role in this. Overall, these results serve as an important reference for the discovery and design of new HDAC6 inhibitors.