A quantitative structural analysis of AR-42 derivatives as HDAC1 inhibitors for the identification of promising structural contributors

Alteration and abnormal epigenetic mechanisms can lead to the aberration of normal biological functions and the occurrence of several diseases. The histone deacetylase (HDAC) family of enzymes is one of the prime regulators of epigenetic functions modifying the histone proteins, and thus, regulating epigenetics directly. HDAC1 is one of those HDACs which have important contributions to cellular epigenetics. The abnormality of HDAC is correlated to the occurrence, progression, and poor prognosis in several disease conditions namely neurodegenerative disorders, cancer cell proliferation, metastasis, chemotherapy resistance, and survival in various cancers. Therefore, the progress of potent and effective HDAC1 inhibitors is one of the prime approaches to combat such diseases. In this study, both regression and classification-based molecular modelling studies were conducted on some AR-42 derivatives as HDAC1 inhibitors to elucidate the crucial structural aspects that are responsible for regulating their biological responses. This study revealed that the molecular polarizability, van der Waals volume, the presence of aromatic rings as well as the higher number of hydrogen bond acceptors might affect prominently their inhibitory activity and might be responsible for proper fitting and interactions at the HDAC1 active site to pertain effective inhibition.