Abstract
Histone acetylation and deacetylation play an essential role in the epigenetic regulation of gene expression. Histone deacetylases (HDAC) are a group of zinc-binding metalloenzymes that catalyze the removal of acetyl moieties from lysine residues from histone tails. These enzymes are well known for their wide spread biological effects in eukaryotes. In rice blast fungus, Magnaporthe oryzae, MoRPD3 (an ortholog of Saccharomyces cerevisiae Rpd3) was shown to be required for growth and development. Thus in this study, the class I HDAC, MoRpd3 is considered as a potential drug target, and its 3D structure was modelled and validated. Based on the model, a total of 1880 compounds were virtually screened (molecular docking) against MoRpd3 and the activities of the compounds were assessed by docking scores. The in silico screening suggested that [2-[[4-(2-methoxyethyl) phenoxy] methyl] phenyl] boronic acid (−8.7 kcal/mol) and [4-[[4-(2-methoxyethyl) phenoxy] methyl] phenyl] boronic acid (−8.5 kcal/mol) are effective in comparison to trichostatin A (−7.9 kcal/mol), a well-known general HDAC inhibitor. The in vitro studies for inhibition of appressorium formation by [2-[[4-(2-methoxyethyl) phenoxy] methyl] phenyl] boronic acid has resulted in the maximum inhibition at lower concentrations (1 μM), while the trichostatin A exhibited similar levels of inhibition at 1.5 μM. These findings thus suggest that 3D quantitative structure activity relationship studies on [2-[[4-(2-methoxyethyl) phenoxy] methyl] phenyl] boronic acid compound can further guide the design of more potential and specific HDAC inhibitors.
Highlights
During the last few decades, extensive work on how epigenetic factors such as histone acetylation contribute to the regulation of gene expression has been carried out
Such histone acetylation is a dynamic and reversible process that is mediated by the concerted activity of histone acetyltransferases (HAT) and histone deacetylases (HDAC) [1]
We found that MoRPD3 that belongs to putative class I HDAC gene is required for vegetative growth and appressorium formation, a key process in M. oryzae infection
Summary
During the last few decades, extensive work on how epigenetic factors such as histone acetylation contribute to the regulation of gene expression has been carried out. Such histone acetylation is a dynamic and reversible process that is mediated by the concerted activity of histone acetyltransferases (HAT) and histone deacetylases (HDAC) [1] These enzymes are well known for their wide-spread biological and developmental effects in higher organisms [2,3,4]. We found that deletion of the RPD3 gene (MoRPD3) in the rice blast fungus, Magnaporthe oryzae, renders the fungus inviable (unpublished data) This line of evidences suggests that RPD3 could be a promising target for identification and development of new agrochemicals that can effectively control fungal diseases in crop plants. Two novel inhibitors identified from our virtual screening were tested for their ability to inhibit fungal growth and appresorium formation
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