2. Academic Validation
  3. X-ray crystal structures, density functional theory and docking on deacetylase enzyme for antiproliferative activity of hispolon derivatives on HCT116 colon cancer

X-ray crystal structures, density functional theory and docking on deacetylase enzyme for antiproliferative activity of hispolon derivatives on HCT116 colon cancer

  • Bioorg Med Chem. 2019 Sep 1;27(17):3805-3812. doi: 10.1016/j.bmc.2019.07.008.
Miriam Rossi 1,  Francesco Caruso 2,  Ilaria Costanzini 3,  Carmen Kloer 2,  Aron Sulovari 2,  Elena Monti 4,  Marzia Gariboldi 4,  Emanuela Marras 4,  Neduri V Balaji 5,  Modukuri V Ramani 5,  Gottumukkala V Subbaraju 6
Affiliations

Affiliations

  • 1 Vassar College, Department of Chemistry, Poughkeepsie NY 12604, USA. Electronic address: rossi@vassar.edu.
  • 2 Vassar College, Department of Chemistry, Poughkeepsie NY 12604, USA.
  • 3 Vassar College, Department of Chemistry, Poughkeepsie NY 12604, USA; University of Modena and Reggio Emilia, Dipartimento di Scienze della Vita, 41121 Modena, Italy.
  • 4 University of Insubria, Department of Biotechnology and Life Sciences,. Via L. Manara 7, 21052 Busto Arsizio, Varese, Italy.
  • 5 Natsol Laboratories Private Limited, Research & Development Building, Ramky Commercial Hub, J. N. Pharmacity, Visakhapatnam 531019, India.
  • 6 Natsol Laboratories Private Limited, Research & Development Building, Ramky Commercial Hub, J. N. Pharmacity, Visakhapatnam 531019, India. Electronic address: subbarajugv@gmail.com.
PMID: 31326241 DOI: 10.1016/j.bmc.2019.07.008
Abstract

The antiproliferative action of hispolon derivatives is stronger than that of related curcumin against several tumor cell lines. Hispolon size, smaller than curcumin, fits better than curcumin into the active site of HDAC6, an Enzyme involved in deacetylation of lysine residues. HDACs are considered potential targets for tumor drug discovery and hydroxamates are known inhibitors of HDACs. One of them, SAHA (Vorinostat) is used in clinical studies. Investigations into possible mechanisms for hispolon derivatives active against the HCT116 colon tumor cell line are done after examining the structural results obtained from hispolon X-ray crystal structures as well as performing associated computational docking and Density Functional Theory techniques on HDAC6. These studies show preference for the HDAC6 active site by chelating the Zn center, in contrast with Other ineffective hispolon derivatives, that establish only a single bond to the metal center. Structure activity relationships make clear that hydrogenation of the hispolon bridge also leads to single bond (non chelate) hispolon-Zn binding, and consistently nullifies the antiproliferative action against HCT116 tumor.

Keywords

Crystal; Curcumin; DFT; Deacetylase; Docking; HCT116; Hispolon.

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