Class I histone deacetylase inhibition by aryl butenoic acid derivatives: In silico and in vitro studies

Abstract

ABSTRACT: Histone deacetylases (HDAC) are evolutionary conserved enzymes, which catalyze removal of acetylgroups from histone and non-histone proteins, therefore, control multiple biological processes. Inhibition of theiractivities have been investigated to modify gene expression and/or protein functions not only for treatment of certaindiseases but also for understanding functions of deacetylase isoforms. We previously synthesized aryl butenoic acidderivatives and identified their pan-HDAC inhibition activities. In this study, we investigated selective inhibitionactivities of these derivatives (C1, C3, C4) on class I HDACs using in silico and in vitro approaches. Molecular dockingstudies of the three aryl butenoic acid derivatives were performed on the crystal structures of HDAC 1, 2, 3 and 8, whichwere obtained from RCSB protein databank, using Glide software. In vitro inhibition activities of the compounds at twodifferent concentrations were tested using fluorometric assay. In silico results indicated that all the compounds showedhigher affinity to HDAC 1 and 8 than other class I deacetylases. In vitro analysis showed that the compounds inhibitHDAC 8 more effectively than HDAC 1. It was shown that C1 had higher binding affinity and inhibition activity to bothenzymes. We concluded that, C1 inhibited both HDAC 1 and 8, however, C3 and C4 showed slight selectivity for HDAC8 over HDAC 1, which was in agreement with the docking studies. Further cell culture studies will be valuable todetermine increased acetylation on target proteins in response to compound treatment.