<i>In silico</i> Design of Novel Histone Deacetylase 4 Inhibitors: Design Guidelines for Improved Binding Affinity

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...

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Main Authors:	Shana V. Stoddard, Kyra Dodson, Kamesha Adams, Davita L. Watkins
Format:	Article
Language:	English
Published:	MDPI AG 2019-12-01
Series:	International Journal of Molecular Sciences
Subjects:	hdac molecular docking inhibitor design molecular interactions glioma hdac4
Online Access:	https://www.mdpi.com/1422-0067/21/1/219

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spelling	doaj-143b67136713462cbb9ec571839c879d2020-11-25T01:50:51ZengMDPI AGInternational Journal of Molecular Sciences1422-00672019-12-0121121910.3390/ijms21010219ijms21010219<i>In silico</i> Design of Novel Histone Deacetylase 4 Inhibitors: Design Guidelines for Improved Binding AffinityShana V. Stoddard0Kyra Dodson1Kamesha Adams2Davita L. Watkins3Department of Chemistry, Natural Sciences Division, Rhodes College, 2000 North Parkway, Memphis, TN 38112, USADepartment of Chemistry and Biochemistry, College of Libera Arts, University of Mississippi, P.O. Box 1848, Oxford, MS 38677, USADepartment of Chemistry, Division of Natural and Mathematical Sciences, LeMoyne-Owen College, 807 Walker Avenue, Memphis, TN 38126, USADepartment of Chemistry and Biochemistry, College of Libera Arts, University of Mississippi, P.O. Box 1848, Oxford, MS 38677, USAHistone 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 <i>in silico</i>. 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.https://www.mdpi.com/1422-0067/21/1/219hdacmolecular dockinginhibitor designmolecular interactionsgliomahdac4
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Shana V. Stoddard Kyra Dodson Kamesha Adams Davita L. Watkins
spellingShingle	Shana V. Stoddard Kyra Dodson Kamesha Adams Davita L. Watkins <i>In silico</i> Design of Novel Histone Deacetylase 4 Inhibitors: Design Guidelines for Improved Binding Affinity International Journal of Molecular Sciences hdac molecular docking inhibitor design molecular interactions glioma hdac4
author_facet	Shana V. Stoddard Kyra Dodson Kamesha Adams Davita L. Watkins
author_sort	Shana V. Stoddard
title	<i>In silico</i> Design of Novel Histone Deacetylase 4 Inhibitors: Design Guidelines for Improved Binding Affinity
title_short	<i>In silico</i> Design of Novel Histone Deacetylase 4 Inhibitors: Design Guidelines for Improved Binding Affinity
title_full	<i>In silico</i> Design of Novel Histone Deacetylase 4 Inhibitors: Design Guidelines for Improved Binding Affinity
title_fullStr	<i>In silico</i> Design of Novel Histone Deacetylase 4 Inhibitors: Design Guidelines for Improved Binding Affinity
title_full_unstemmed	<i>In silico</i> Design of Novel Histone Deacetylase 4 Inhibitors: Design Guidelines for Improved Binding Affinity
title_sort	<i>in silico</i> design of novel histone deacetylase 4 inhibitors: design guidelines for improved binding affinity
publisher	MDPI AG
series	International Journal of Molecular Sciences
issn	1422-0067
publishDate	2019-12-01
description	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 <i>in silico</i>. 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.
topic	hdac molecular docking inhibitor design molecular interactions glioma hdac4
url	https://www.mdpi.com/1422-0067/21/1/219
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<i>In silico</i> Design of Novel Histone Deacetylase 4 Inhibitors: Design Guidelines for Improved Binding Affinity

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