title: Structure-Based Drug Discovery for Prion Disease Using a Novel Binding Simulation.
abstract: 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 the 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.
authors.affiliation: Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Japan. Electronic address: dishi@nagasaki-u.ac.jp.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ishibashi
authors.affiliation: Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Nakagaki
authors.affiliation: Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ishikawa
authors.affiliation: Division of Microbiology, Department of Infectious Diseases, Faculty of Medicine, University of Miyazaki, Japan.
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Atarashi
authors.affiliation: Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Nagasaki Advanced Computing Center, Nagasaki University, Japan.
authors.forename: Felipe A
authors.initials: FA
authors.lastname: Cruz
authors.affiliation: Nagasaki Advanced Computing Center, Nagasaki University, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Hamada
authors.affiliation: Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Nishida
mesh_terms: D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D055808:Drug Discovery; D006801:Humans; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D062105:Molecular Docking Simulation; D017096:Prion Diseases; D000072002:Prion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism*; D020349:Surface Plasmon Resonance; D013816:Thermodynamics
chemical_list: D000072002:Prion Proteins; D011994:Recombinant Proteins; D054852:Small Molecule Libraries
keywords: Conformational disorders; Drug discovery; In silico screening; Prion; Small chemical compounds