Histone Deacetylase 8 (HDAC8) decreases gene expression by coiling DNA on histone proteins. When overactive, HDAC8 can silence tumor suppressor genes and, therefore, aid in the development of certain cancers. This study investigates the depsipeptide class of HDAC inhibitors (HDACi), the most potent HDACi found to date, through computational methods. One such depsipeptide inhibitor, Romidepsin, has been approved for chemotherapy uses by the FDA and is a selective inhibitor of Class I HDACs which include HDACs 1, 2, 3, and 8. Understanding enzyme-inhibitor interactions provides insight for future design and synthesis of more potent and selective HDACi resulting in a more effective drug with less harsh side effects. Conformational sampling was performed with MODELLER to provide a flexibility component in the protein for docking. Using AutoDock4 supplemented with the AutoDock4Zn force field, the structures of the HDAC-Romidepsin complexes were determined. Interestingly, a large majority of the dockings showed Romidepsin “capping” the active site of the protein. This contradicts the generally accepted binding in which the thiol of Romidepsin binds to the catalytic zinc of HDAC8; there is no known crystal structures of Romidepsin in any HDAC, however. Preliminary computational studies have shown that certain modifications allow for better binding to the catalytic zinc of HDAC8, similar to other depsipeptide inhibitors.

Molecular modeling of histone deacetylase complexes

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.