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Open AccessArticle

In silico Design of Novel Histone Deacetylase 4 Inhibitors: Design Guidelines for Improved Binding Affinity

1
Department of Chemistry, Natural Sciences Division, Rhodes College, 2000 North Parkway, Memphis, TN 38112, USA
2
Department of Chemistry and Biochemistry, College of Libera Arts, University of Mississippi, P.O. Box 1848, Oxford, MS 38677, USA
3
Department of Chemistry, Division of Natural and Mathematical Sciences, LeMoyne-Owen College, 807 Walker Avenue, Memphis, TN 38126, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(1), 219; https://doi.org/10.3390/ijms21010219
Received: 25 November 2019 / Revised: 19 December 2019 / Accepted: 25 December 2019 / Published: 28 December 2019
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease II)
Histone deacetylases (HDAC) are being targeted for a number of diseases such as cancer, inflammatory disease, and neurological disorders. Within this family of 18 isozymes, HDAC4 is a prime target for glioma, one of the most aggressive brain tumors reported. Thus, the development of HDAC4 inhibitors could present a novel therapeutic route for glioma. In this work, molecular docking studies on cyclopropane hydroxamic acid derivatives identified five novel molecular interactions to the HDAC4 receptor that could be harnessed to enhance inhibitor binding. Thus, design guidelines for the optimization of potent HDAC4 inhibitors were developed which can be utilized to further the development of HDAC4 inhibitors. Using the developed guidelines, eleven novel cyclopropane hydroxamic acid derivatives were designed that outcompeted all original cyclopropane hydroxamic acids HDAC4 inhibitors studied in silico. The results of this work will be an asset to paving the way for further design and optimization of novel potent HDAC4 inhibitors for gliomas. View Full-Text
Keywords: HDAC; molecular docking; inhibitor design; molecular interactions; glioma; HDAC4 HDAC; molecular docking; inhibitor design; molecular interactions; glioma; HDAC4
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MDPI and ACS Style

V. Stoddard, S.; Dodson, K.; Adams, K.; L. Watkins, D. In silico Design of Novel Histone Deacetylase 4 Inhibitors: Design Guidelines for Improved Binding Affinity. Int. J. Mol. Sci. 2020, 21, 219.

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