Thursday, August 28, 2025

Structure-based rational design of covalent probes

Holcomb, M., Llanos, M., Hansel-Harris, A. et al. 

Commun Chem 8, 242 (2025). 

https://doi.org/10.1038/s42004-025-01606-y

Covalent probes are becoming increasingly important to both fundamental biology and drug design, as what was once an idiosyncrasy at best and a source of toxicity at worst has transitioned to a paradigm for drug discovery. However, these covalent probes offer different challenges for the incorporation of structural data into the design process than do non-covalent probes, whose activity may be captured by very few bound states. In this review, we discuss the role of structure-based design in the discovery and optimization of covalent probes, with a special emphasis on computational methods to leverage structural data.

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H. T. Rosen ,  K. Li ,  C. E. Stieger ,  E. L. Li ,  B. Currier ,  S. M. Brittain ,  F. J. Garcia ,  D. C. Beard ,  M. D. Jones ,  S. Haenni...