The Chemical Tuning of a Weak Zinc Binding Motif for Histone Deacetylase Using Electronic Effects.
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Mccarren, Patrick, Whitehead, Lewis and Hall, Michelle (2012) The Chemical Tuning of a Weak Zinc Binding Motif for Histone Deacetylase Using Electronic Effects. Chemical Biology & Drug Design. ISSN 1747-0277
Abstract
Though hydroxamic acids have been effective warheads for targeting HDAC enzymes, they are generally associated with severe side effects. Therefore, much work has been directed towards discovering novel binding motifs. Computational screening approaches must typically utilize quantum mechanics energies or reparameterized force fields to account for the metal binding group. Wiest and coworkers recently used a minimal binding site model with quantum mechanics calculations to suggest a previously undisclosed 2-aminoketone motif as a weak zinc-binding motif. However, the approach failed to identify the correct binding mode and did not suggest how to improve the binding of this motif. The current article details modifications of the approach to capture the weaker, secondary interaction of the ketone and shows that the underlying energy calculations must be treated with care. The model binding site approach has a better chance of identifying relative binding of metal binding motifs and the deficiencies identified are also present in the commonly used QM/MM approaches. The path to finding better zinc binding through electronic structure methods is presented in the scheme of the highly tunable 2-aminoketone motif.
| Item Type: | Article |
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| Additional Information: | author can archive post-print (ie final draft post-refereeing); On personal web site or secure external website at authors institution; Publisher's version/PDF cannot be used |
| Keywords: | in silico, QM, HDAC, HDAC8, DFT |
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| Date Deposited: | 13 Oct 2015 13:14 |
| Last Modified: | 13 Oct 2015 13:14 |
| URI: | https://oak.novartis.com/id/eprint/7074 |