Discovery of Sulfated Small Molecule Inhibitors of Matrix Metalloproteinase-8
Elevated matrix metalloproteinase-8 (MMP-8) activity contributes to the etiology of many diseases, including atherosclerosis, pulmonary fibrosis, and sepsis. Yet, very few small molecule inhibitors of MMP-8 have been identified. We reasoned that the synthetic non-sugar mimetics of glycosaminoglycans...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-08-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/10/8/1166 |
| _version_ | 1797559347884064768 |
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| author | Shravan Morla Umesh R. Desai |
| author_facet | Shravan Morla Umesh R. Desai |
| author_sort | Shravan Morla |
| collection | DOAJ |
| description | Elevated matrix metalloproteinase-8 (MMP-8) activity contributes to the etiology of many diseases, including atherosclerosis, pulmonary fibrosis, and sepsis. Yet, very few small molecule inhibitors of MMP-8 have been identified. We reasoned that the synthetic non-sugar mimetics of glycosaminoglycans may inhibit MMP-8 because natural glycosaminoglycans are known to modulate the functions of various MMPs. The screening a library of 58 synthetic, sulfated mimetics consisting of a dozen scaffolds led to the identification of only two scaffolds, including sulfated benzofurans and sulfated quinazolinones, as promising inhibitors of MMP-8. Interestingly, the sulfated quinazolinones displayed full antagonism of MMP-8 and sulfated benzofuran appeared to show partial antagonism. Of the two, sulfated quinazolinones exhibited a >10-fold selectivity for MMP-8 over MMP-9, a closely related metalloproteinase. Molecular modeling suggested the plausible occupancy of the S<sub>1</sub><sup>′</sup> pocket on MMP-8 as the distinguishing feature of the interaction. Overall, this work provides the first proof that the sulfated mimetics of glycosaminoglycans could lead to potent, selective, and catalytic activity-tunable, small molecular inhibitors of MMP-8. |
| first_indexed | 2024-03-10T17:44:00Z |
| format | Article |
| id | doaj.art-9caa7f2a395b49cdafa5bbf56f5ddf18 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T17:44:00Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-9caa7f2a395b49cdafa5bbf56f5ddf182023-11-20T09:35:39ZengMDPI AGBiomolecules2218-273X2020-08-01108116610.3390/biom10081166Discovery of Sulfated Small Molecule Inhibitors of Matrix Metalloproteinase-8Shravan Morla0Umesh R. Desai1Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298, USADepartment of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298, USAElevated matrix metalloproteinase-8 (MMP-8) activity contributes to the etiology of many diseases, including atherosclerosis, pulmonary fibrosis, and sepsis. Yet, very few small molecule inhibitors of MMP-8 have been identified. We reasoned that the synthetic non-sugar mimetics of glycosaminoglycans may inhibit MMP-8 because natural glycosaminoglycans are known to modulate the functions of various MMPs. The screening a library of 58 synthetic, sulfated mimetics consisting of a dozen scaffolds led to the identification of only two scaffolds, including sulfated benzofurans and sulfated quinazolinones, as promising inhibitors of MMP-8. Interestingly, the sulfated quinazolinones displayed full antagonism of MMP-8 and sulfated benzofuran appeared to show partial antagonism. Of the two, sulfated quinazolinones exhibited a >10-fold selectivity for MMP-8 over MMP-9, a closely related metalloproteinase. Molecular modeling suggested the plausible occupancy of the S<sub>1</sub><sup>′</sup> pocket on MMP-8 as the distinguishing feature of the interaction. Overall, this work provides the first proof that the sulfated mimetics of glycosaminoglycans could lead to potent, selective, and catalytic activity-tunable, small molecular inhibitors of MMP-8.https://www.mdpi.com/2218-273X/10/8/1166matrix metalloproteinasesglycosaminoglycanssmall molecule inhibitorsdrug discovery |
| spellingShingle | Shravan Morla Umesh R. Desai Discovery of Sulfated Small Molecule Inhibitors of Matrix Metalloproteinase-8 Biomolecules matrix metalloproteinases glycosaminoglycans small molecule inhibitors drug discovery |
| title | Discovery of Sulfated Small Molecule Inhibitors of Matrix Metalloproteinase-8 |
| title_full | Discovery of Sulfated Small Molecule Inhibitors of Matrix Metalloproteinase-8 |
| title_fullStr | Discovery of Sulfated Small Molecule Inhibitors of Matrix Metalloproteinase-8 |
| title_full_unstemmed | Discovery of Sulfated Small Molecule Inhibitors of Matrix Metalloproteinase-8 |
| title_short | Discovery of Sulfated Small Molecule Inhibitors of Matrix Metalloproteinase-8 |
| title_sort | discovery of sulfated small molecule inhibitors of matrix metalloproteinase 8 |
| topic | matrix metalloproteinases glycosaminoglycans small molecule inhibitors drug discovery |
| url | https://www.mdpi.com/2218-273X/10/8/1166 |
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