**4. Conclusions**

The present study shows, for the first time, the possibility of inhibiting MMP-8 by targeting electropositive GAG binding sites, and identifies two new small molecule GAG-mimicking sulfated scaffolds, the sulfated benzofurans and sulfated quinazolinones, as inhibitors of MMP-8. Of these, the sulfated benzofurans appear to be broad-spectrum MMP inhibitors because of their engagement of the catalytic Zn2<sup>+</sup> and histidines. In contrast, the sulfated quinazolinones bind in the S<sup>1</sup> ′ pocket of MMP-8, thereby enhancing the selectivity of inhibition. Considering that several NSGM-based initial hits have been transformed through hit-to-lead optimization strategies into potent and selective candidates [30,36], the potential to transform NSGM **38** into a promising drug-like candidate or a chemical biology tool is high.

**Supplementary Materials:** The following are available online at http://www.mdpi.com/2218-273X/10/8/1166/s1: Figure S1: Comparison of the mode of binding of **38** and **43** on MMP-8. Figure S2: Mode of binding of the top five NSGM inhibitors (**26**, **38**, **40**, **41**, and **42**) of MMP-8 (shown in ESP map). Table S1: General structure of MMP-8 inhibitors developed to date, Table S2: List of interactions made by NSGMs with MMP-8.

**Author Contributions:** S.M. performed the library screening, inhibition, and computational studies, and wrote the initial draft of the manuscript; U.R.D. finalized the manuscript, acquired funding, and directed the project. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was supported by grants HL090586, HL107152, and CA241951 from the National Institute of Health to U.R.D.

**Conflicts of Interest:** The authors declare no conflict of interest.
