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Histone deacetylase inhibitors (HDACi) have demonstrated emerging therapeutic potential in cancer treatment by inhibiting the activity of histone deacetylase enzymes (HDACs)1. Currently, only a limited number of HDACi have been approved by drug regulators for use as anticancer drugs. SAHA, a hydroxamic acid, was the first drug approved in 2007 by the FDA as an anticancer agent2. Chidamide 3, a benzamide, was approved by drug regulators in China in 2014 and in Japan in 2021 for the treatment of peripheral T-cell lymphoma. Several other benzamides, including mocetinostat, entinostat, and zabadinostat 4,5, are currently undergoing clinical trials. Benzamides, as zinc-dependent inhibitors of histone deacetylases (HDACi), bind to the active site of the HDAC enzyme. Even though these molecules are chemically different, they all work in a similar way: their functional group binds to the metal ion in the active site of the histone deacetylase enzyme. Several important questions regarding the physicochemical properties and metal affinities/selectivities of the benzamide-based HDACi (Chidamide, Mocetinostat, Entinostat, and Zabadinostat) considered in this study remain unanswered. First, what is the preferred geometry of the studied benzamide-based HDACi? Second, how do the structural factors influence the affinity/selectivity of these molecules when binding to essential metal cations? Last, but not least, what is the preferred mode of binding to the metal ions? The study utilized density functional theory calculations and polarizable continuum model computations to study the physicochemical properties of the selected benzamide-based HDACi. The geometry of selected benzamide-based HDACi, along with their binding patterns and metal affinity/selectivity, was studied. Furthermore, the results obtained revealed the key factors that govern their metal-ligating capabilities and the thermodynamics of the binding of benzamide-based HDACi to different biogenic metal ions (Zn2+, Fe2+, and Mg2+) providing insights for improving their metal-ligating properties.
(1) Barneda-Zahonero, B.; Parra, M. Histone deacetylases and cancer. Molecular Oncology 2012, 6 (6), 579-589, Review. DOI: 10.1016/j.molonc.2012.07.003. (2) Mann, B. S.; Johnson, J. R.; Cohen, M. H.; Justice, R.; Pazdur, R. FDA approval summary: Vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 2007, 12 (10), 1247-1252, Article. DOI: 10.1634/theoncologist.12-10-1247. (3) Shi, Y.; Dong, M.; Hong, X.; Zhang, W.; Feng, J.; Zhu, J.; Yu, L.; Ke, X.; Huang, H.; Shen, Z.; et al. Results from a multicenter, open-label, pivotal phase II study of chidamide in relapsed or refractory peripheral T-cell lymphoma. Annals of Oncology 2015, 26 (8), 1766-1771. DOI: 10.1093/annonc/mdv237. (4) Liu, G.; Barczak, W.; Lee, L.; Shrestha, A.; Provine, N.; Albayrak, G.; Zhu, H.; Hutchings, C.; Klenerman, P.; La Thangue, N. The HDAC inhibitor zabadinostat is a systemic regulator of adaptive immunity. COMMUNICATIONS BIOLOGY 2023, 6 (1). DOI: 10.1038/s42003-023-04485-y. (5) Tian, X.; Wang, T.; Shen, H.; Wang, S. Tumor microenvironment, histone modifications, and myeloid-derived suppressor cells. CYTOKINE & GROWTH FACTOR REVIEWS 2023, 74, 108-121. DOI: 10.1016/j.cytogfr.2023.08.002.
Acknowledgments: 1. The research that led to these results was carried out using the infrastructure purchased under the National Roadmap for RI, financially coordinated by the MES of the Republic of Bulgaria (grant No D01-325/01.12.2023), 2.This research is supported by the Bulgarian Ministry of Education and Science under the National Program „Young Scientists and Postdoctoral Students-2”.
