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.
Prion; Drug discovery; In silico screening; Small chemical compounds; Conformational disorders
Citation: Daisuke Ishibashia, Takehiro Nakagakia, Takeshi Ishikawaa, Ryuichiro Atarashib, Ken Watanabea, Felipe A. Cruzc, Tsuyoshi Hamadac, Noriyuki Nishidaa Structure-based Drug Discovery For Prion Disease Using A Novel Binding Simulation doi:10.1016/j.ebiom.2016.06.010
Received: 28 April 2016, Revised: 25 May 2016, Accepted: 6 June 2016, Available online: 8 June 2016
Copyright: © 2016 The Authors. 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/).
The authors declare that they have no competing interests.
Author contribution statement
D.I., T.N., T.I., F.C. and T.H. coordinated and performed the entire project. R.A., K.W. and N.N. supervised and discussed the data. D.I., T.N. and T.I wrote the manuscript. D.I. and N.N. revised the manuscript.
We thank Dr. Yoshimasa Tanaka and Prof. Katsuya Satoh from Nagasaki University and Dr. Yuji O. Kamatari from Gifu University for helpful discussions and critical assessment of the manuscript, and Hanako Nakayama, Ayako Nakazaki, Atsuko Matsuo and Megumi Tanaka for technical assistance. This work was supported by a Grant-in-Aid of the Research Committee of Prion Disease and Slow Virus Infection from the Ministry of Health, Labor and Welfare of Japan; a Grant-in-Aid of the Research Committee of Molecular Pathogenesis and Therapies for Prion Disease and Slow Virus Infection, the Practical Research Project for Rare and Intractable Disease from the Japan Agency for Medical Research and Development, AMED; a grant from the Takeda Science Foundation; a grant from the Japan Intractable Disease Research Foundation; a Grant-in-Aid from the Tokyo Biochemical Research Foundation; and a grant provided by the YOKOYAMA Foundation for Clinical Pharmacology (Grant No. YRY1502).