@article{cfda031a230c411980190f60787b5029,
title = "A virtual screening platform identifies chloroethylagelastatin a as a potential ribosomal inhibitor",
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.",
keywords = "Agelastatin A, Cancer treatment, Chloroethylagelastatin A, Computational screening, Ribosome",
author = "Caulfield, {Thomas R.} and Hayes, {Karen E.} and Yushi Qiu and Mathew Coban and Oh, {Joon Seok} and Lane, {Amy L.} and Takehiko Yoshimitsu and Lori Hazlehurst and Copland, {John A.} and Tun, {Han W.}",
note = "Funding Information: T.Y. received funding from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) grant number KAKENHI #15K14977, The NOVARTIS Foundation (Japan) for the Promotion of Science, and the Hoansha Foundation. H.T., J.C., and L.H. received funding by NCI STTR program grant number R41 CA210669-01A1. T.C. thanks the NIH LRP program and the Center for Individualized Medicine at Mayo Clinic for supporting time to work on this endeavor. H.T. thanks Martha G. Bagby foundation for generous support for therapeutic development research. Funding Information: Funding: T.Y. received funding from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) grant number KAKENHI #15K14977, The NOVARTIS Foundation (Japan) for the Promotion of Science, and the Hoansha Foundation. H.T., J.C., and L.H. received funding by NCI STTR program grant number R41 CA210669-01A1. Funding Information: Acknowledgments: T.C. thanks the NIH LRP program and the Center for Individualized Medicine at Mayo Clinic for supporting time to work on this endeavor. H.T. thanks Martha G. Bagby foundation for generous support for therapeutic development research. Publisher Copyright: {\textcopyright} 2020 by the authors.",
year = "2020",
month = oct,
doi = "10.3390/biom10101407",
language = "English",
volume = "10",
pages = "1--19",
journal = "Biomolecules",
issn = "2218-273X",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "10",
}
