Monday, September 16, 2019

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

Angus Voice, Gary Tresadern, Herman Van Vlijmen and Adrian J. Mulholland

J. Chem. Inf. Model. 2019


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 ,-unsaturated carbonyl compounds that form covalent adducts with cysteine. We demonstrate that, whilst these metrics correlate well with experiment for a diverse range of covalent fragments, 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 intra-molecular interactions.

Oncogenic KRAS G12C: Kinetic and Redox Characterization of Covalent Inhibition

Minh V. Huynh, Derek Parsonage, Tom E. Forshaw, Venkat R. Chirasani, G. Aaron Hobbs, Hanzhi Wu, Jingyun Lee, Cristina M. Furdui, Leslie B. P...