A virtual screening platform identifies chloroethylagelastatin a as a potential ribosomal inhibitor

Thomas R. Caulfield, Karen E. Hayes, Yushi Qiu, Mathew Coban, Joon Seok Oh, Amy L. Lane, Takehiko Yoshimitsu, Lori Hazlehurst, John A. Copland, Han W. Tun

Research output: Contribution to journalArticlepeer-review

Abstract

Chloroethylagelastatin A (CEAA) is an analogue of agelastatin A (AA), a natural alkaloid derived from a marine sponge. It is under development for therapeutic use against brain tumors as it has excellent central nervous system (CNS) penetration and pre-clinical therapeutic activity against brain tumors. Recently, AA was shown to inhibit protein synthesis by binding to the ribosomal A-site. In this study, we developed a novel virtual screening platform to perform a comprehensive screening of various AA analogues showing that AA analogues with proven therapeutic activity including CEAA have significant ribosomal binding capacity whereas therapeutically inactive analogues show poor ribosomal binding and revealing structural fingerprint features essential for drug-ribosome interactions. In particular, CEAA was found to have greater ribosomal binding capacity than AA. Biological tests showed that CEAA binds the ribosome and contributes to protein synthesis inhibition. Our findings suggest that CEAA may possess ribosomal inhibitor activity and that our virtual screening platform may be a useful tool in discovery and development of novel ribosomal inhibitors.

Original languageEnglish
Article number1407
Pages (from-to)1-19
Number of pages19
JournalBiomolecules
Volume10
Issue number10
DOIs
Publication statusPublished - Oct 2020

Keywords

  • Agelastatin A
  • Cancer treatment
  • Chloroethylagelastatin A
  • Computational screening
  • Ribosome

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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