Polymerizable Matrix Metalloproteinases’ Inhibitors with Potential Application for Dental Restorations
Abstract
:1. Introduction
2. Materials and Methods
2.1. Computational Docking Studies
2.2. Synthesis of A, B and C Compounds
2.3. Cytotoxicity Study Using MTT Assay
2.4. Statistical Analysis
3. Results and Discussion
3.1. Docking Studies
3.1.1. Physicochemical and ADMET Properties of NNGH Commercial Inhibitor, Compounds A, B and C
3.1.2. Interactions between Ligand and Protein
Collagenases (MMP-1, -8 and -13)
Gelatinases (MMP-2 and -9)
3.2. Cytotoxicity Study
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
Appendix A
Parameter | NNGH | Compound A | Compound B | Compound C |
---|---|---|---|---|
MW | 316.375 | 263.295 | 349.428 | 336.389 |
H-bonds acceptors | 6 | 3 | 4 | 2 |
H-bonds donors | 2 | 0 | 0 | 2 |
Aromatic rings | 1 | 2 | 2 | 2 |
Stereo centers | 0 | 0 | 0 | 0 |
Rotatable bonds | 5 | 0 | 6 | 0 |
Total charge | 0 (OH)/ −1 (O−) | 0 | 0 | 0 |
Log P | 1.472 | 3.828 | 5.089 | 2.943 |
Log D | −0.075 | 3.828 | 5.089 | 2.943 |
TPSA | 95.94 | 50.09 | 59.32 | 67.43 |
BBB category | − | + | + | − |
BBB log ([brain]:[blood]) | 0.703 | −0.158 | −0.150 | −0.492 |
P-gp category | No | No | No | Yes |
2C9 pki | 4.377 | 4.931 | 5.040 | 5.125 |
2D6 affinity | Low | Medium | High | Medium |
HIA category | + | + | + | + |
PPB90 category | Low | High | High | High |
hERG pIC50 | 4.319 | 5.073 | 5.749 | 4.894 |
Log S (pH = 7.4) | 3.264 | 0.653 | -0.217 | 2.336 |
Appendix B
Appendix C
Appendix D
Appendix E
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MMP | PDB ID | Total Structure Weight (kDa) | Method | Resolution (Å) | R-Factor (%) |
---|---|---|---|---|---|
1 | 2tcl | 19.63 | X-ray diffraction | 2.20 | 16.2 |
2 | 1HOV | 19.28 | Solution NMR | − | − |
8 | 1BZS | 19.22 | X-ray diffraction | 1.70 | 19.2 |
9 | 4XCT | 18.97 | X-ray diffraction | 1.30 | 17.0 |
13 | 1FM1 | 19.21 | Solution NMR | − | − |
Property | NNGH | Compound A | Compound B | Compound C |
---|---|---|---|---|
Molecular weight (MW) | 316.375 | 263.295 | 349.428 | 336.389 |
H-bonds acceptor | 6 | 3 | 4 | 2 |
H-bonds donor | 2 | 0 | 0 | 2 |
Log P | 1.472 | 3.828 | 5.089 | 2.943 |
Log D | −0.075 | 3.828 | 5.089 | 2.943 |
Topological polar surface area (TPSA) | 95.94 | 50.09 | 59.32 | 67.43 |
BBB category | − | + | + | − |
BBB log[(brain): (blood)] | 0.703 | −0.158 | −0.15 | −0.492 |
P-gp category | No | No | No | Yes |
Residue | NNGH | Compound A | Compound B | Compound C |
---|---|---|---|---|
Leu81 (MMP-1); Leu160 (MMP-8); Leu82 (MMP-13) | All collagenases | All collagenases | MMP-8 MMP-13 | MMP-8 |
Ala82 (MMP-1); Ala161 (MMP-8); Ala83 (MMP-13) | All collagenases | MMP-1 | MMP-8 MMP-13 | MMP-8 MMP-13 |
Ala84 (MMP-1); Ala163 (MMP-8); Ala85 (MMP-13) | No interact | MMP-13 | MMP-1 | All collagenases |
Groups | Cell Viability (%) | ||||
---|---|---|---|---|---|
Inhibitor Compound | Inhibitor Concentration | NIH/3T3 | MG-63 | ||
M | SD | M | SD | ||
A | 20 μM | 85.1 | 0.71 | 82.6 | 2.28 |
50 µM | 54.2 | 4.47 | 73.6 | 0.78 | |
100 µM | 45.5 | 5.30 | 73.0 | 5.40 | |
B | 20 µM | 78.6 | 1.41 | 78.1 | 1.41 |
50 µM | 50.5 | 4.42 | 70.3 | 2.03 | |
100 µM | 40.5 | 1.60 | 65.9 | 0.82 | |
C | 20 µM | 83.7 | 1.41 | 85.0 | 0.36 |
50 µM | 46.4 | 4.22 | 65.8 | 2.94 | |
100 µM | 42.4 | 8.28 | 69.2 | 9.24 |
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Laronha, H.; Carpinteiro, I.; Portugal, J.; Azul, A.; Polido, M.; Petrova, K.T.; Salema-Oom, M.; Barahona, I.; Caldeira, J. Polymerizable Matrix Metalloproteinases’ Inhibitors with Potential Application for Dental Restorations. Biomedicines 2021, 9, 366. https://doi.org/10.3390/biomedicines9040366
Laronha H, Carpinteiro I, Portugal J, Azul A, Polido M, Petrova KT, Salema-Oom M, Barahona I, Caldeira J. Polymerizable Matrix Metalloproteinases’ Inhibitors with Potential Application for Dental Restorations. Biomedicines. 2021; 9(4):366. https://doi.org/10.3390/biomedicines9040366
Chicago/Turabian StyleLaronha, Helena, Inês Carpinteiro, Jaime Portugal, Ana Azul, Mário Polido, Krasimira T. Petrova, Madalena Salema-Oom, Isabel Barahona, and Jorge Caldeira. 2021. "Polymerizable Matrix Metalloproteinases’ Inhibitors with Potential Application for Dental Restorations" Biomedicines 9, no. 4: 366. https://doi.org/10.3390/biomedicines9040366