Albany 2015:Book of Abstracts
June 9-13 2015
©Adenine Press (2012)
Histone Deacetylase (HDAC) I Catalytic core Asp-His Charge Relay System is altered by HDAC inhibitors: Atomistic Simulation Studies
Histone deacetylases (HDACs) are representative target for cell transforming natural and synthetic chemicals with antitumor properties. In the current study, curcumin and hydroxamate-derivative PCI-34058 bound HDAC1 have been subjected to atomistic simulation. The results support that the fitting of the curcumin and PCI-34058 within HDAC1 pocket resulted from extensive interactions between the aromatic moieties of the inhibitors and the extensive network of aromatic amino acid side chains lining the pocket of HDAC1. The interaction forced a local perturbation of the coiled structures connecting the pocket residues resulting in ligand-induced tightening of the pocket. In addition to the competitive occupancy of the histone-acetyl-lysine binding pocket by the inhibitors, interference with the in-pocket Histidine-Aspartate charge relay system was also observed in inhibitor bound HDAC1 systems. In conclusion, curcumin and PCI-34058-mediate ligand-dependent HDAC1 tunnel closure, negatively interfere with the ASP-HIS charge relay system in HDAC1. Future designs of HDAC inhibitors may benefit from optimizing competitive interaction with ligand site and interference with charge relay system.
I. O. Omotuyi 1, 2
1Pharmacology and Therapeutic Innovation