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Molecular Dynamics Simulation Study Explaining Inhibitor Selectivity in Different Class of Histone Deacetylases

Histone deacetylases (HDACs) are key regulators of gene expression and thereby compelling targets in the treatment of various cancers. Class- and isoform-selective HDAC inhibitors targeting the particular isoform to treat cancers without affecting the normal expression of other isoforms are highly desirable. Molecular dynamics simulations were performed with the set of selective inhibitors and HDAC isoforms of three different classes. The results were compared both within and across the isoforms. The hydrogen bonds between protein and inhibitors are directly correlated with the selective experimental activity. The calculated distances between important amino acids and the metal binding part of inhibitors have disclosed the optimal distance to be maintained by a selective inhibitor. In addition, the calculated non-bonded interaction energies between inhibitor and catalytic residues revealed that the subtle difference in the amino acids at the highly conserved active sites of HDAC isoforms effectively scripts the selectivity story observed experimentally. The results of this study provide valuable information in designing highly selective HDAC inhibitors.

Key words: Histone deacetylase; Inhibitor selectivity; Molecular dynamic simulation; Drug design; Non-bonded interaction energy.

This article can be cited as:
S. Thangapandian, S. John, K.W. Lee. Molecular Dynamics Simulation Study Explaining Inhibitor Selectivity in Different Class of Histone Deacetylases J. Biomol Struct Dyn 29(4), 677-698 (2012).

Sundarapandian Thangapandian
Shalini John
Keun Woo Lee*

Division of Applied Life Science (BK21 Program), Systems and Synthetic Agrobiotech Center (SSAC), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Gazha-dong, Jinju 660-701, Republic of Korea

*Corresponding author:
Keun Woo Lee
Phone: 182 55 772 1360
Fax: 182 55 772 1359
E-mail: kwlee@gnu.ac.kr

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