Structure-Based Discovery of Small Molecule Inhibitors of Cariogenic Virulence

Abstract Streptococcus mutans employs a key virulence factor, three glucosyltransferase (GtfBCD) enzymes to establish cariogenic biofilms. Therefore, the inhibition of GtfBCD would provide anti-virulence therapeutics. Here a small molecule library of 500,000 small molecule compounds was screened in...

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Autores principales:	Qiong Zhang, Bhavitavya Nijampatnam, Zhang Hua, Thao Nguyen, Jing Zou, Xia Cai, Suzanne M. Michalek, Sadanandan E. Velu, Hui Wu
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/fd06f20a37b34ee2a6b0c326fa712604
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spelling	oai:doaj.org-article:fd06f20a37b34ee2a6b0c326fa7126042021-12-02T12:32:20ZStructure-Based Discovery of Small Molecule Inhibitors of Cariogenic Virulence10.1038/s41598-017-06168-12045-2322https://doaj.org/article/fd06f20a37b34ee2a6b0c326fa7126042017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06168-1https://doaj.org/toc/2045-2322Abstract Streptococcus mutans employs a key virulence factor, three glucosyltransferase (GtfBCD) enzymes to establish cariogenic biofilms. Therefore, the inhibition of GtfBCD would provide anti-virulence therapeutics. Here a small molecule library of 500,000 small molecule compounds was screened in silico against the available crystal structure of the GtfC catalytic domain. Based on the predicted binding affinities and drug-like properties, small molecules were selected and evaluated for their ability to reduce S. mutans biofilms, as well as inhibit the activity of Gtfs. The most potent inhibitor was further characterized for Gtf binding using OctetRed instrument, which yielded low micromolar KD against GtfB and nanomolar KD against GtfC, demonstrating selectivity towards GtfC. Additionally, the lead compound did not affect the overall growth of S. mutans and commensal oral bacteria, and selectively inhibit the biofilm formation by S. mutans, indicative of its selectivity and non-bactericidal nature. The lead compound also effectively reduced cariogenicity in vivo in a rat model of dental caries. An analog that docked poorly in the GtfC catalytic domain failed to inhibit the activity of Gtfs and S. mutans biofilms, signifying the specificity of the lead compound. This report illustrates the validity and potential of structure-based design of anti-S. mutans virulence inhibitors.Qiong ZhangBhavitavya NijampatnamZhang HuaThao NguyenJing ZouXia CaiSuzanne M. MichalekSadanandan E. VeluHui WuNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Qiong Zhang Bhavitavya Nijampatnam Zhang Hua Thao Nguyen Jing Zou Xia Cai Suzanne M. Michalek Sadanandan E. Velu Hui Wu Structure-Based Discovery of Small Molecule Inhibitors of Cariogenic Virulence
description	Abstract Streptococcus mutans employs a key virulence factor, three glucosyltransferase (GtfBCD) enzymes to establish cariogenic biofilms. Therefore, the inhibition of GtfBCD would provide anti-virulence therapeutics. Here a small molecule library of 500,000 small molecule compounds was screened in silico against the available crystal structure of the GtfC catalytic domain. Based on the predicted binding affinities and drug-like properties, small molecules were selected and evaluated for their ability to reduce S. mutans biofilms, as well as inhibit the activity of Gtfs. The most potent inhibitor was further characterized for Gtf binding using OctetRed instrument, which yielded low micromolar KD against GtfB and nanomolar KD against GtfC, demonstrating selectivity towards GtfC. Additionally, the lead compound did not affect the overall growth of S. mutans and commensal oral bacteria, and selectively inhibit the biofilm formation by S. mutans, indicative of its selectivity and non-bactericidal nature. The lead compound also effectively reduced cariogenicity in vivo in a rat model of dental caries. An analog that docked poorly in the GtfC catalytic domain failed to inhibit the activity of Gtfs and S. mutans biofilms, signifying the specificity of the lead compound. This report illustrates the validity and potential of structure-based design of anti-S. mutans virulence inhibitors.
format	article
author	Qiong Zhang Bhavitavya Nijampatnam Zhang Hua Thao Nguyen Jing Zou Xia Cai Suzanne M. Michalek Sadanandan E. Velu Hui Wu
author_facet	Qiong Zhang Bhavitavya Nijampatnam Zhang Hua Thao Nguyen Jing Zou Xia Cai Suzanne M. Michalek Sadanandan E. Velu Hui Wu
author_sort	Qiong Zhang
title	Structure-Based Discovery of Small Molecule Inhibitors of Cariogenic Virulence
title_short	Structure-Based Discovery of Small Molecule Inhibitors of Cariogenic Virulence
title_full	Structure-Based Discovery of Small Molecule Inhibitors of Cariogenic Virulence
title_fullStr	Structure-Based Discovery of Small Molecule Inhibitors of Cariogenic Virulence
title_full_unstemmed	Structure-Based Discovery of Small Molecule Inhibitors of Cariogenic Virulence
title_sort	structure-based discovery of small molecule inhibitors of cariogenic virulence
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/fd06f20a37b34ee2a6b0c326fa712604
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Structure-Based Discovery of Small Molecule Inhibitors of Cariogenic Virulence

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