2. Academic Validation
  3. Structure-Based Discovery of Small Molecule Inhibitors of Cariogenic Virulence

Structure-Based Discovery of Small Molecule Inhibitors of Cariogenic Virulence

  • Sci Rep. 2017 Jul 20;7(1):5974. doi: 10.1038/s41598-017-06168-1.
Qiong Zhang 1 2,  Bhavitavya Nijampatnam 3,  Zhang Hua 1,  Thao Nguyen 3,  Jing Zou 1,  Xia Cai 4,  Suzanne M Michalek 4,  Sadanandan E Velu 5,  Hui Wu 6 7
Affiliations

Affiliations

  • 1 Department of Pediatric Dentistry, University of Alabama at Birmingham, School of Dentistry, Birmingham, Alabama, 35294, USA.
  • 2 Department of Pediatric Dentistry, West China Hospital of Stomatology, State Key Laboratory of Oral Diseases, Sichuan University, Chengdu, Sichuan, 610041, P.R. China.
  • 3 Department of Chemistry, University of Alabama at Birmingham, 901, 14th Street S, Birmingham, AL, 35294, USA.
  • 4 Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
  • 5 Department of Chemistry, University of Alabama at Birmingham, 901, 14th Street S, Birmingham, AL, 35294, USA. svelu@uab.edu.
  • 6 Department of Pediatric Dentistry, University of Alabama at Birmingham, School of Dentistry, Birmingham, Alabama, 35294, USA. hwu@uab.edu.
  • 7 Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA. hwu@uab.edu.
PMID: 28729722 DOI: 10.1038/s41598-017-06168-1
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.

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