Tuesday, July 18, 2023

Proteome-wide structural analysis identifies warhead-and coverage-specific biases in cysteine-focused chemoproteomics

Matthew E H White, Jesús Gil, Edward W Tate

https://doi.org/10.1016/j.chembiol.2023.06.021

Covalent drug discovery has undergone a resurgence over the past two decades and reactive cysteine profiling has emerged in parallel as a platform for ligand discovery through on- and off-target profiling; however, the scope of this approach has not been fully explored at the whole-proteome level. We combined AlphaFold2-predicted side-chain accessibilities for >95% of the human proteome with a meta-analysis of eighteen public cysteine profiling datasets, totaling 44,187 unique cysteine residues, revealing accessibility biases in sampled cysteines primarily dictated by warhead chemistry. Analysis of >3.5 million cysteine-fragment interactions further showed that hit elaboration and optimization drives increased bias against buried cysteine residues. Based on these data, we suggest that current profiling approaches cover a small proportion of potential ligandable cysteine residues and propose future directions for increasing coverage, focusing on high-priority residues and depth. All analysis and produced resources are freely available and extendable to other reactive amino acids.



Rapid, potent, and persistent covalent chemical probes to deconvolute PI3Kα signaling

Lukas Bissegger,  Theodora A. Constantin,  Erhan Keles,  Luka Raguž,   Isobel Barlow-Busch,  Clara Orbegozo,   Thorsten Schaefer,  Valentina...