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Computational exploration of zinc binding groups for HDAC inhibition.

ABSTRACT: Histone deacetylases (HDACs) have emerged as important drug targets in epigenetics. The most common HDAC inhibitors use hydroxamic acids as zinc binding groups despite unfavorable pharmacokinetic properties. A two-stage protocol of M05-2X calculations of a library of 48 fragments in a small model active site, followed by QM/MM hybrid calculations of the full enzyme with selected binders, is used to prospectively select potential bidentate zinc binders. The energetics and interaction patterns of several zinc binders not previously used for the inhibition of HDACs are discussed.

SUBMITTER: Chen K

PROVIDER: S-EPMC3703144 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Computational exploration of zinc binding groups for HDAC inhibition.

Chen Kai K Xu Liping L Wiest Olaf O

The Journal of organic chemistry 20130429 10

Histone deacetylases (HDACs) have emerged as important drug targets in epigenetics. The most common HDAC inhibitors use hydroxamic acids as zinc binding groups despite unfavorable pharmacokinetic properties. A two-stage protocol of M05-2X calculations of a library of 48 fragments in a small model active site, followed by QM/MM hybrid calculations of the full enzyme with selected binders, is used to prospectively select potential bidentate zinc binders. The energetics and interaction patterns of ...[more]

PMID: 23586590

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