Protein-Directed Dynamic Combinatorial Chemistry: A Guide to Protein Ligand and Inhibitor Discovery
Abstract
:1. Introduction
2. The Protein-Directed DCC Method
2.1. General Concept
2.2. Composition of a Dynamic Combinatorial Library
2.3. Reversible Reactions and Reaction Conditions for Protein-Directed DCC
2.4. Protein Template
2.5. Analytical Techniques
3. Summary and Outlook
Acknowledgments
Author Contributions
Conflicts of Interest
Abbreviations
2OG | 2-Oxoglutarate |
ATP | Adenosine triphosphate |
DCC | Dynamic combinatorial chemistry |
DCL | Dynamic combinatorial library |
DNA | Deoxyribonucleic acid |
FITC | Fluorescein isothiocyanate |
GABA | γ-Animobytyric acid |
GAT1 | γ-Animobytyric acid transporter 1 |
HEWL | Hen egg-white lysozyme |
HIF | Hypoxia inducible factor |
HPLC | High-performance liquid chromatography |
HSP | Heat shock protein |
HTS | High-throughput screening |
JMJD2 | Jumonji domain 2 |
LC-MS | Liquid chromatography-mass spectrometry |
NMR | Nuclear magnetic resonance |
NOE | Nuclear Overhauser effect |
PHD2 | Prolyl hydroxylase domain 2 |
STD | Saturation transfer difference |
TPR | Tetratricopeptide repeat |
WaterLOGSY | Water ligand-observed via gradient spectroscopy |
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Compound(s) | KD/μM | IC50/μM |
---|---|---|
Boronic acid ‘scaffold ligand’ | 24.8 | 126 |
Boronate ester conjugate | 18.2 * | N/A |
Boronate ester conjugate | 3.0 * | N/A |
Boronate ester conjugate | 0.8 * | N/A |
First generation stable analogue | 7.0 | >500 |
First generation stable analogue | 1.6 | 107 |
Second generation stable analogue | 0.5 | 0.017 |
Second generation stable analogue | 0.8 | 0.013 |
Peptide | rac-A2B (KD/μM) | meso-A2B (KD/μM) |
---|---|---|
H3 K9Me3 | 25 ± 3 | 28 ± 4 |
H3 K9Me2 | 58 ± 10 | 73 ± 9 |
H3 K9 Me | 166 ± 50 | not determined |
H3 K9 | >1200 | not determined |
Reaction | Scheme | Notes |
---|---|---|
Imine formation |
| |
Hydrazone formation |
| |
Thiol-disulphide exchange |
| |
Thiol-enone exchange |
| |
Hemithioacetal reaction |
| |
Boronate ester formation |
|
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Huang, R.; Leung, I.K.H. Protein-Directed Dynamic Combinatorial Chemistry: A Guide to Protein Ligand and Inhibitor Discovery. Molecules 2016, 21, 910. https://doi.org/10.3390/molecules21070910
Huang R, Leung IKH. Protein-Directed Dynamic Combinatorial Chemistry: A Guide to Protein Ligand and Inhibitor Discovery. Molecules. 2016; 21(7):910. https://doi.org/10.3390/molecules21070910
Chicago/Turabian StyleHuang, Renjie, and Ivanhoe K. H. Leung. 2016. "Protein-Directed Dynamic Combinatorial Chemistry: A Guide to Protein Ligand and Inhibitor Discovery" Molecules 21, no. 7: 910. https://doi.org/10.3390/molecules21070910