Structural exploration of common pharmacophore based berberine derivatives as novel histone deacetylase inhibitor targeting HDACs enzymes

Histone deacetylase (HDAC) inhibitors, are new class of cancer chemotherapeutics used in clinical development. It plays a pivotal role in restoring the acetylation balance and lysine residual deacetylation in histone and non-histone proteins. Notably, HDAC inhibitors have been approved by FDA to treat different malignancies. Recently, we demonstrated berberine as pan inhibitor for HDAC. However, isoform specific inhibition of HDAC enzyme is highly warranted. Therefore, a pharmacophore based structural exploration of berberine is in need to be developed, berberine is composed of four portions namely: a) zinc binding group (ZBG), b) Linker (scaffold), c) connect unit (CU), and d) surface recognition moiety (SRM). We derived four berberine derivatives based on common HDAC inhibition pharmacophore, compound 4 possesses highest bit score by molecular docking and compound stability by HOMOs-LUMOs analysis. It is concluded that, structurally modified berberine derivatives shown better inhibition of HDAC enzymes offering improved clinical efficacy.