Docking Approaches Used in Epigenetic Drug Investigations

Epigenetics is a term referred to heritable modification which does not involve mutations or translocations on DNA sequence; but at molecular level, structural modifications on nucleic acids or histone proteins occur. These modifications are carried out by proteins known as “writer, " “readers, " and “erasers.” Writers add covalent modifications, readers recognize these chemical modifications, and erasers remove these modifications. Epigenetic dysregulation is associated with diseases genesis or development, such as cancer, metabolic, cardiovascular, immune, and neurodegenerative diseases. Therefore, these protein families are under extensive investigation as they are considered as pharmacological targets. So, several research groups around the world are designing molecules to target these pharmacological targets. The use of theoretical calculations including docking in drug design research is essential, as it guides the ligand design both with reduced time and economical cost. Molecular docking predicts the binding properties of ligands on biological targets (generally proteins). There are several classes of epigenetic targets and their inhibitors: DNA methyltransferase (DNMT) inhibitors, histone acetyltransferase (HAT) inhibitors, histone lysine methyltransferase (HKMT) inhibitors, histone deacetylase (HDAC) inhibitors, histone lysine demethylase (HKDM) inhibitors, bromodomain inhibitors. DNMT inhibitors have been discovered from natural or synthetic sources employing molecular docking from rational design or by virtual screening. With HAT, several successful cases have recently been reported such as the case of curcumin derivatives targeting CBP, HAT, or a high-throughput screening identifying GCN5 inhibitors. In terms of HKMT inhibitors, several approaches were employed not only targeting human HKMT such as G9a but also other organisms such as Plasmodium falciparum. For HKDM inhibitors, the use of molecular docking has led to deferiprone as HKDM inhibitor and also the discovery of a Jumonji demethylase inhibitor. In terms of bromodomain inhibitors, natural products such as flavonoids and some commercial compounds have been discovered using docking. Finally, HDACs are one of the most explored molecular targets, and several molecules were discovered by docking.