Novel GH-20 β-N-acetylglucosaminidase inhibitors: Virtual screening, molecular docking, binding affinity, and anti-tumor activity

Piyanat Meekrathok, Sunisa Thongsom, Anuwat Aunkham, Anuphon Kaewmaneewat, Yoshihito Kitaoku, Kiattawee Choowongkomon, Wipa Suginta

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

β-N-acetylglucosaminidases (GlcNAcases) play a crucial role in the metabolism of glycan-conjugated proteins/lipids in humans. Elevated levels of serum GlcNAcases have been associated with certain types of cancer, and GlcNAcases therefore serve as drug targets. Here, we employed virtual screening to identify two novel GlcNAcase inhibitors from the National Cancer Institute (NCI) Drug Library using a bacterial GH-20 GlcNAcase (VhGlcNAcase) as a search model. NSC73735 was shown to be most potent with IC50 of 12.7 ± 1.2 μM, agreeing with Kd of 0.94 ± 0.2 μM obtained by ITC. Molecular docking refinement indicated that Trp582 the key residue that interacted with all the inhibitor molecules. Docking NSC7373 into the active site of human O-GlcNAcase (hOGA) yielded reasonably good fit with the estimated Kd of 44.7 µM, indicating its possibility to be a true binding partner. NSC73735 was shown to significantly suppress both cell growth and GlcNAcase activity of five cancer cell lines (U937, THP-1, MCF-7, HepG2 and PC-3) that express endogenous GlcNAcases. The cell cytotoxicity assay indicated the inherent effects of the lead compound on GlcNAcase expression with cancer cell proliferation, and therefore this novel GlcNAcase inhibitor may serve as a virtuous candidate for further development of highly potent anti-tumor agents.

Original languageEnglish
Pages (from-to)503-512
Number of pages10
JournalInternational Journal of Biological Macromolecules
Volume142
DOIs
Publication statusPublished - Jan 1 2020
Externally publishedYes

Keywords

  • Acetylglucosaminidase/antagonists & inhibitors
  • Antineoplastic Agents/metabolism
  • Cell Line, Tumor
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors/metabolism
  • Humans
  • Molecular Docking Simulation
  • Protein Conformation
  • User-Computer Interface

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