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

Daisuke Ishibashi, Takehiro Nakagaki, Takeshi Ishikawa, Ryuichiro Atarashi, Ken Watanabe, Felipe A. Cruz, Tsuyoshi Hamada, Noriyuki Nishida
2016 EBioMedicine  
The accumulation of abnormal prion protein (PrP Sc ) converted from the normal cellular isoform of PrP (PrP C ) 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
more » ... e candidates showing a high-binding score, the compounds exhibited direct interaction with recombinant PrP in vitro, and drastically reduced PrP Sc 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 PrP C binding as the intermolecular interaction mode. Furthermore, PrP Sc 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.
doi:10.1016/j.ebiom.2016.06.010 pmid:27333028 pmcid:PMC4972544 fatcat:mcj46kg4lbch7hp4kd2kdiqw74