Factors governing the affinity and selectivity of histone deacetylase inhibitors for the HDAC8 enzyme active site: Implications for anticancer therapy

  1. Nikolay Toshev,
  2. Diana CheshmedzhievaORCID Logo and
  3. Todor DudevORCID Logo

Submitting author affiliation: University of Sofia, Sofia, Bulgaria

Beilstein Arch. 2020, 2020121. https://doi.org/10.3762/bxiv.2020.121.v1

Published 21 Oct 2020

  • Preprint

Abstract

Disruptions in post-translational modifications of chromatin structure promote uncontrollable cell growth branded as a hallmark of tumor lesions. The overexpression/hyperactivity of histone deacetylases (HDACs) is a common feature for the tumorogenesis and cancer progression. Several inhibitors of histone deacetylases (mainly hydroxamic acid derivatives) have been successfully used as drugs in fighting tumor formations. However, there is no systematic study on the factors controling the affinity and selectivity of this type of inhibitors to the host enzyme thus hampering successful rational design of more potent and selective anticancer drugs. Herein, in an attempt to illuminate the mechanism of the host – guest interactions in these systems at atomic level we systematically study the effect of various factors in the process and unravel its key determinants.  Density functional theory calculations have been employed. Our findings have the potential to be employed as guidelines in designing new HDAC inhibitors with improved anticancer properties.

Keywords: Cancer; Density Functional Theory; Histone Deacetylase Inhibitors; Molecular Modeling; SAHA;

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When a peer-reviewed version of this preprint is available, this information will be updated in the information box above. If no peer-reviewed version is available, please cite this preprint using the following information:

Toshev, N.; Cheshmedzhieva, D.; Dudev, T. Beilstein Arch. 2020, 2020121. doi:10.3762/bxiv.2020.121.v1

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© 2020 Toshev et al.; licensee Beilstein-Institut.
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