TY - JOUR
T1 - Structure-Based Discovery of Small Molecule Inhibitors of Cariogenic Virulence
AU - Zhang, Qiong
AU - Nijampatnam, Bhavitavya
AU - Hua, Zhang
AU - Nguyen, Thao
AU - Zou, Jing
AU - Cai, Xia
AU - Michalek, Suzanne M.
AU - Velu, Sadanandan E.
AU - Wu, Hui
N1 - Funding Information:
We would also like to thank Dr. Rebecca Boohaker and the Southern Research Institute for the use of the OctetRed instrument. This study was funded by the National Institute of Dental and Craniofacial Research, National Institutes of Health R01DE022350 (HW), R03DE025058 (SV), and the National Natural Science Foundation of China 81400502 (QZ).
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41598-017-06168-1
DO - 10.1038/s41598-017-06168-1
M3 - Article
C2 - 28729722
AN - SCOPUS:85025462913
SN - 2045-2322
VL - 7
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 5974
ER -