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

• Ishibashi, Daisuke

• Nakagaki, Takehiro

• Ishikawa, Takeshi

• Atarashi, Ryuichiro

• Watanabe, Ken

• Cruz, Felipe A.

• Hamada, Tsuyoshi

• Nishida, Noriyuki

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.

EBioMedicine, 9, pp.238-249; 2016

Journal

• EBioMedicine

  EBioMedicine 9 238-249, 2016-07

  Elsevier B.V.

Keywords

• Conformational disorders
• Drug discovery
• In silico screening
• Prion
• Small chemical compounds

Details

• CRID: 1050568772240579328
• NII Article ID: 120006987627
• ISSN: 23523964
• DOI: 10.1016/j.ebiom.2016.06.010
• HANDLE: 10069/37328
• Web Site: https://nagasaki-u.repo.nii.ac.jp/records/2132
• Web Site: https://api.elsevier.com/content/article/PII:S2352396416302547?httpAccept=text/xml
• Web Site: https://api.elsevier.com/content/article/PII:S2352396416302547?httpAccept=text/plain
• Text Lang: en
• Article Type: journal article
• Data Source:
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