title: Discovery of Novel Anti-prion Compounds Using In Silico and In Vitro Approaches.
abstract: Prion diseases are associated with the conformational conversion of the physiological form of cellular prion protein (PrP(C)) to the pathogenic form, PrP(Sc). Compounds that inhibit this process by blocking conversion to the PrP(Sc) could provide useful anti-prion therapies. However, no suitable drugs have been identified to date. To identify novel anti-prion compounds, we developed a combined structure- and ligand-based virtual screening system in silico. Virtual screening of a 700,000-compound database, followed by cluster analysis, identified 37 compounds with strong interactions with essential hotspot PrP residues identified in a previous study of PrP(C) interaction with a known anti-prion compound (GN8). These compounds were tested in vitro using a multimer detection system, cell-based assays, and surface plasmon resonance. Some compounds effectively reduced PrP(Sc) levels and one of these compounds also showed a high binding affinity for PrP(C). These results provide a promising starting point for the development of anti-prion compounds.
authors.affiliation: Division of Zoonoses, Center for Immunology &Pathology, National Institute of Health, Korea Centers for Disease Control &Prevention, Chungcheongbuk-do 363-700, Korea.
authors.forename: Jae Wook
authors.initials: JW
authors.lastname: Hyeon
authors.affiliation: Bioinformatics &Molecular Design Research Center, Seoul, 120-749, Korea.
authors.forename: Jiwon
authors.initials: J
authors.lastname: Choi
authors.affiliation: Division of Zoonoses, Center for Immunology &Pathology, National Institute of Health, Korea Centers for Disease Control &Prevention, Chungcheongbuk-do 363-700, Korea.
authors.forename: Su Yeon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Bioinformatics &Molecular Design Research Center, Seoul, 120-749, Korea.
authors.forename: Rajiv Gandhi
authors.initials: RG
authors.lastname: Govindaraj
authors.affiliation: Division of Zoonoses, Center for Immunology &Pathology, National Institute of Health, Korea Centers for Disease Control &Prevention, Chungcheongbuk-do 363-700, Korea.
authors.forename: Kyu
authors.initials: K
authors.lastname: Jam Hwang
authors.affiliation: Division of Zoonoses, Center for Immunology &Pathology, National Institute of Health, Korea Centers for Disease Control &Prevention, Chungcheongbuk-do 363-700, Korea.
authors.forename: Yeong Seon
authors.initials: YS
authors.lastname: Lee
authors.affiliation: GachonBioNano Research Institute, Gachon University, Gyeonggi-do 461-701, Korea.
authors.forename: Seong Soo A
authors.initials: SS
authors.lastname: An
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju 361-763, Korea.
authors.forename: Myung Koo
authors.initials: MK
authors.lastname: Lee
authors.affiliation: Nano/Bio Computational Chemistry Laboratory, Department of Chemistry, Sookmyung Woman's University, Seoul, 140-742, Korea.
authors.forename: Jong Young
authors.initials: JY
authors.lastname: Joung
authors.affiliation: Bioinformatics &Molecular Design Research Center, Seoul, 120-749, Korea.|Department of Biotechnology, Yonsei University, Seoul, 120-749, Korea.
authors.forename: Kyoung Tai
authors.initials: KT
authors.lastname: No
authors.affiliation: Division of Zoonoses, Center for Immunology &Pathology, National Institute of Health, Korea Centers for Disease Control &Prevention, Chungcheongbuk-do 363-700, Korea.
authors.forename: Jeongmin
authors.initials: J
authors.lastname: Lee
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003198:Computer Simulation; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D018621:PrPC Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018620:PrPSc Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D017096:Prion Diseases / Q000188:drug therapy / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020349:Surface Plasmon Resonance; D015262:Xenobiotics / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*
chemical_list: D008024:Ligands; D018621:PrPC Proteins; D018620:PrPSc Proteins; D015262:Xenobiotics