MOLECULAR DOCKING, ADMET, AND MOLECULAR DYNAMICS SIMULATION STUDIES FOR MOLECULES WITH EXPECTED HDAC INHIBITION ACTIVITY

Abstract

Background: Histone deacetylases (HDACs) are promising epigenetic target for the treatment of a variety of diseases including cancer, inflammations, and neurological disorders. A number of. HDAC inhibitors have been approved for the treatment of cancer. Most of the HDAC inhibitors have poor pharmacokinetic properties such as short half-life, fast metabolism, and clearance. To overcome this limitation, several attempts are ongoing to develop new molecules with unique zinc binding groups. The objective is to design and evaluate new compounds featuring heterocyclic ring-based zinc binding groups (ZBGs) targeting histone deacetylases (HDACs) for potential therapeutic use in various diseases, including cancer, inflammations, and neurological disorders. The expected zinc chelation activity for ZBG in addition the construction of the linker and the cap group were evaluated using molecular modeling studies.

Materials & Methods: A series of new compounds with promising HDAC inhibition activities were designed based on a molecular modeling to improve the HDACs inhibitory potency, improving pharmacokinetic properties, and conferring cancer cell targeting. Twenty new compounds (K1-K20) were designed via special modification of common structural activity relationship (SAR) of HDAC inhibitors using heterocyclic rings as a zinc binding group (ZBG), diverse group in cap group, and hydrophobic linker. These compounds were analyzed by docking study, ADMET, and molecular dynamics (MD) simulations against HDAC isoforms using vorinostat as a reference.

Results: The docking study revealed that the proposed compounds haves higher docking score than vorinostat. All molecules were showed promising virtual HDACs binding affinity. The ADMET analysis of the designed compound showed acceptable pharmacokinetics results. In comparison to vorinostat, the MD simulation analysis revealed that compound K1 had significantly perfect alignment to HDAC8.

Conclusions: The precise virtual binding affinity for K1 might be attributed to the unique chelation capacity of the amino group of imidazole ZBG of K1 with zinc metal cofactor of HDACs enzymes, other interaction of linker with surrounding amino acid residues, and the presence of fused aromatic ring in cap group.