In silico, in vitro, X-ray crystallography, and integrated strategies for discovering spermidine synthase inhibitors for Chagas disease

Abstract Chagas disease results from infection by Trypanosoma cruzi and is a neglected tropical disease (NTD). Although some treatment drugs are available, their use is associated with severe problems, including adverse effects and limited effectiveness during the chronic disease phase. To develop a...

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Autores principales:	Ryunosuke Yoshino, Nobuaki Yasuo, Yohsuke Hagiwara, Takashi Ishida, Daniel Ken Inaoka, Yasushi Amano, Yukihiro Tateishi, Kazuki Ohno, Ichiji Namatame, Tatsuya Niimi, Masaya Orita, Kiyoshi Kita, Yutaka Akiyama, Masakazu Sekijima
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9864fe2ce67f43499bde2b3251ec52d6
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spelling	oai:doaj.org-article:9864fe2ce67f43499bde2b3251ec52d62021-12-02T15:06:05ZIn silico, in vitro, X-ray crystallography, and integrated strategies for discovering spermidine synthase inhibitors for Chagas disease10.1038/s41598-017-06411-92045-2322https://doaj.org/article/9864fe2ce67f43499bde2b3251ec52d62017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06411-9https://doaj.org/toc/2045-2322Abstract Chagas disease results from infection by Trypanosoma cruzi and is a neglected tropical disease (NTD). Although some treatment drugs are available, their use is associated with severe problems, including adverse effects and limited effectiveness during the chronic disease phase. To develop a novel anti-Chagas drug, we virtually screened 4.8 million small molecules against spermidine synthase (SpdSyn) as the target protein using our super computer “TSUBAME2.5” and conducted in vitro enzyme assays to determine the half-maximal inhibitory concentration values. We identified four hit compounds that inhibit T. cruzi SpdSyn (TcSpdSyn) by in silico and in vitro screening. We also determined the TcSpdSyn–hit compound complex structure using X-ray crystallography, which shows that the hit compound binds to the putrescine-binding site and interacts with Asp171 through a salt bridge.Ryunosuke YoshinoNobuaki YasuoYohsuke HagiwaraTakashi IshidaDaniel Ken InaokaYasushi AmanoYukihiro TateishiKazuki OhnoIchiji NamatameTatsuya NiimiMasaya OritaKiyoshi KitaYutaka AkiyamaMasakazu SekijimaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-9 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ryunosuke Yoshino Nobuaki Yasuo Yohsuke Hagiwara Takashi Ishida Daniel Ken Inaoka Yasushi Amano Yukihiro Tateishi Kazuki Ohno Ichiji Namatame Tatsuya Niimi Masaya Orita Kiyoshi Kita Yutaka Akiyama Masakazu Sekijima In silico, in vitro, X-ray crystallography, and integrated strategies for discovering spermidine synthase inhibitors for Chagas disease
description	Abstract Chagas disease results from infection by Trypanosoma cruzi and is a neglected tropical disease (NTD). Although some treatment drugs are available, their use is associated with severe problems, including adverse effects and limited effectiveness during the chronic disease phase. To develop a novel anti-Chagas drug, we virtually screened 4.8 million small molecules against spermidine synthase (SpdSyn) as the target protein using our super computer “TSUBAME2.5” and conducted in vitro enzyme assays to determine the half-maximal inhibitory concentration values. We identified four hit compounds that inhibit T. cruzi SpdSyn (TcSpdSyn) by in silico and in vitro screening. We also determined the TcSpdSyn–hit compound complex structure using X-ray crystallography, which shows that the hit compound binds to the putrescine-binding site and interacts with Asp171 through a salt bridge.
format	article
author	Ryunosuke Yoshino Nobuaki Yasuo Yohsuke Hagiwara Takashi Ishida Daniel Ken Inaoka Yasushi Amano Yukihiro Tateishi Kazuki Ohno Ichiji Namatame Tatsuya Niimi Masaya Orita Kiyoshi Kita Yutaka Akiyama Masakazu Sekijima
author_facet	Ryunosuke Yoshino Nobuaki Yasuo Yohsuke Hagiwara Takashi Ishida Daniel Ken Inaoka Yasushi Amano Yukihiro Tateishi Kazuki Ohno Ichiji Namatame Tatsuya Niimi Masaya Orita Kiyoshi Kita Yutaka Akiyama Masakazu Sekijima
author_sort	Ryunosuke Yoshino
title	In silico, in vitro, X-ray crystallography, and integrated strategies for discovering spermidine synthase inhibitors for Chagas disease
title_short	In silico, in vitro, X-ray crystallography, and integrated strategies for discovering spermidine synthase inhibitors for Chagas disease
title_full	In silico, in vitro, X-ray crystallography, and integrated strategies for discovering spermidine synthase inhibitors for Chagas disease
title_fullStr	In silico, in vitro, X-ray crystallography, and integrated strategies for discovering spermidine synthase inhibitors for Chagas disease
title_full_unstemmed	In silico, in vitro, X-ray crystallography, and integrated strategies for discovering spermidine synthase inhibitors for Chagas disease
title_sort	in silico, in vitro, x-ray crystallography, and integrated strategies for discovering spermidine synthase inhibitors for chagas disease
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/9864fe2ce67f43499bde2b3251ec52d6
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In silico, in vitro, X-ray crystallography, and integrated strategies for discovering spermidine synthase inhibitors for Chagas disease

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