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Structure-Based Drug Discovery for Prion Disease Using a Novel Binding Simulation

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Title: Structure-Based Drug Discovery for Prion Disease Using a Novel Binding Simulation
Authors: Ishibashi, Daisuke / Nakagaki, Takehiro / Ishikawa, Takeshi / Atarashi, Ryuichiro / Watanabe, Ken / Cruz, Felipe A. / Hamada, Tsuyoshi / Nishida, Noriyuki
Issue Date: Jul-2016
Publisher: Elsevier B.V.
Citation: EBioMedicine, 9, pp.238-249; 2016
Abstract: The accumulation of abnormal prion protein (PrPSc) converted from the normal cellular isoform of PrP (PrPC) is assumed to induce pathogenesis in prion diseases. Therefore, drug discovery studies for these diseases have focused on the protein conversion process. We used a structure-based drug discovery algorithm (termed Nagasaki University Docking Engine: NUDE) that ran on an intensive supercomputer with a graphic-processing unit to identify several compounds with anti-prion effects. Among the candidates showing a high-binding score, the compounds exhibited direct interaction with recombinant PrP in vitro, and drastically reduced PrPSc and protein-aggresomes in the prion-infected cells. The fragment molecular orbital calculation showed that the van der Waals interaction played a key role in PrPC binding as the intermolecular interaction mode. Furthermore, PrPSc accumulation and microgliosis were significantly reduced in the brains of treated mice, suggesting that the drug candidates provided protection from prion disease, although further in vivo tests are needed to confirm these findings. This NUDE-based structure-based drug discovery for normal protein structures is likely useful for the development of drugs to treat other conformational disorders, such as Alzheimer's disease.
Keywords: Conformational disorders / Drug discovery / In silico screening / Prion / Small chemical compounds
URI: http://hdl.handle.net/10069/37328
ISSN: 23523964
DOI: 10.1016/j.ebiom.2016.06.010
Rights: © 2016 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Type: Journal Article
Text Version: publisher
Appears in Collections:Articles in academic journal

Citable URI : http://hdl.handle.net/10069/37328

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