Abstract
Boron-containing molecules have been extensively used for the purposes of chemical sensing, biological probe development and drug discovery. Due to boron's empty p orbital, it can coordinate to heteroatoms such as oxygen and nitrogen. This reversible covalent mode of interaction has led to the use of boron as bait for nucleophilic residues in disease-associated proteins, culminating in the approval of new therapeutics that work by covalent mechanisms. Our analysis of a wide range of covalent inhibitors with electrophilic groups suggests that boron is a unique electrophile in its chameleonic ability to engage protein targets. Here we review boron's interactions with a range of protein side-chain residues and reveal that boron's properties are nuanced and arise from its uncommon coordination preferences. These mechanistic and structural insights should serve as a guide for the development of selective boron-based bioactive molecules.
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Acknowledgements
We would like to thank the Natural Science and Engineering Research Council (NSERC) and the Canadian Institutes of Health Research (CIHR) for financial support. Helpful discussions with Harjeet Soor (UofT) and Frank Lee (UofT) are gratefully appreciated. D.B.D. also thanks NSERC for PGS-D funding.
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Diaz, D., Yudin, A. The versatility of boron in biological target engagement. Nature Chem 9, 731–742 (2017). https://doi.org/10.1038/nchem.2814
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DOI: https://doi.org/10.1038/nchem.2814
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