Structure-based Drug Discovery For Prion Disease Using A Novel Binding Simulation
Authors: Daisuke Ishibashia, Takehiro Nakagakia, Takeshi Ishikawaa, Ryuichiro Atarashib, Ken Watanabea, Felipe A. Cruzc, Tsuyoshi Hamadac, Noriyuki Nishidaa
Abstract:
The pathogenesis of prion diseases is associated with the accumulation of abnormal prion protein (PrPSc), which is derived from the normal cellular isoform of PrP (PrPC). Consequently, drug discovery efforts for these diseases have focused on targeting the protein conversion process. In this study, we employed Nagasaki University Docking Engine (NUDE), a structure-based drug discovery algorithm, running on a high-performance supercomputer equipped with a graphic-processing unit. Through this approach, we identified several compounds exhibiting anti-prion effects.
Among the candidates with high-binding scores, these compounds displayed direct interaction with recombinant PrP in vitro, leading to a significant reduction in PrPSc and protein aggregates in prion-infected cells. Fragment molecular orbital calculations highlighted the crucial role of van der Waals interactions in the binding between the compounds and PrPC. Furthermore, in the brains of treated mice, there was a notable decrease in PrPSc accumulation and microgliosis, suggesting potential protective effects against prion disease. However, further in vivo testing is required to validate these findings.
The success of this NUDE-based structure-based drug discovery, focused on normal protein structures, holds promise for the development of drugs targeting other conformational disorders, including Alzheimer's disease.
Keywords
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/).
Competing interests
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.
Acknowledgments
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).
