Limitations of ligand-only approaches for predicting the reactivity of covalent inhibitors

Angus Voice, Gary Tresadern, Herman van Vlijmen, Adrian J Mulholland

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Covalent inhibition has undergone a resurgence and is an important modern-day drug design and chemical biology approach. To avoid off-target interactions and to fine-tune reactivity, the ability to accurately predict reactivity is vitally important for the design and development of safer and more effective covalent drugs. Several ligand-only metrics have been proposed that promise quick and simple ways of determining covalent reactivity. In particular, we examine proton affinity and reaction energies calculated with the density functional B3LYP-D3/6-311+G**//B3LYP-D3/6-31G* method to assess the reactivity of a series of α,β-unsaturated carbonyl compounds that form covalent adducts with cysteine. We demonstrate that while these metrics correlate well with experiment for a diverse range of small reactive molecules these approaches fail for predicting the reactivity of drug-like compounds. We conclude that ligand-only metrics such as proton affinity and reaction energies do not capture determinants of reactivity in situ and fail to account for important factors such as conformation, solvation, and intermolecular interactions.
Original languageEnglish
Number of pages8
JournalJournal of Chemical Information and Modeling
Early online date24 Sep 2019
Publication statusE-pub ahead of print - 24 Sep 2019


  • Covalent
  • TCI
  • Reactivity prediction
  • Drug discovery,
  • Proton affinity
  • Density Functional Theory

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