Molecular docking evaluation of some analogues of biarylbenzamides as HDAC1 inhibitors for cancer treatment

Introduction & Objectives: Histone deacetylases (HDACs) are attractive therapeutic targets for the treatment of cancer and other diseases. Of the four classes of HDAC found in mammals, HDAC1 has a key role in cancer and overexpressed in different cancers also, the design of HDAC1 inhibitors is an ongoing topic in drug design.Material and Methods: The molecular docking process was performed using Molecular Operation Environment (MOE) software to predict mode of interaction between the best possible biological conformations of compounds in the active site of HDAC1 enzyme. The 2D structures of compounds were prepared by Chem Draw ultra 8.0 software and converted into 3D format by Hyper Chem7 using AM1 semi-empirical method. The compounds were docked into active site of HDAC1 (PDB ID: 4BKX) by MOE software. The best pose of compounds with the higher score was selected for ligand-target interaction analysis by LigX module in MOE software.Results: The docking results showed a high docking score (-15.75 kcal/mol) for the most active compound of biarylbenzamide in comparison to that of the least active compound (-12.45 kcal/mol) and also, HDAC1 enzyme is a zinc-dependent enzyme and zinc atom was penta-coordinated with His178, Asp176and Asp264 as well as the carbonyl and NH2 groups of the compounds.Conclusion: The docking studies showed interaction mode of biarylbenzamide derivatives with HDAC1 including zinc ion coordination, strong hydrophobic interactions and formation of hydrogen bond with benzamides. The amido and amine groups of benzamide part as scaffold and the bulk groups as a hydrophobic part were key factors to improve inhibitory activity of HDAC1 and design more potent HDAC1 inhibitors for the therapeutic of cancer.

کلیدواژه ها:

Histone deacetylase 1 ، BiarylBenzamide ، Molecular Docking ، HDAC1 inhibitors