Quantum Descriptors for Predicting and Understanding the Structure-Activity Relationships of Michael Acceptor Warheads

Predictive modeling and understanding of chemical warheadreactivitieshave the potential to accelerate targeted covalent drug discovery.Recently, the carbanion formation free energies as well as other ground-stateelectronic properties from density functional theory (DFT) calculationshave been proposed as predictors of glutathione reactivities of Michaelacceptors; however, no clear consensus exists. By profiling the thiol-Michaelreactions of a diverse set of singly- and doubly-activated olefins,including several model warheads related to afatinib, here we reexaminedthe question of whether low-cost electronic properties can be usedas predictors of reaction barriers. The electronic properties relatedto the carbanion intermediate were found to be strong predictors,e.g., the change in the C-& beta; charge accompanying carbanionformation. The least expensive reactant-only properties, the electrophilicityindex, and the C-& beta; charge also show strong rank correlations,suggesting their utility as quantum descriptors. A second objectiveof the work is to clarify the effect of the & beta;-dimethylaminomethyl(DMAM) substitution, which is incorporated in the warheads of severalFDA-approved covalent drugs. Our data suggest that the & beta;-DMAMsubstitution is cationic at neutral pH in solution and promotes acrylamide'sintrinsic reactivity by enhancing the charge accumulation at C-& alpha; upon carbanion formation. In contrast, the inductiveeffect of the & beta;-trimethylaminomethyl substitution is diminisheddue to steric hindrance. Together, these results reconcile the currentviews of the intrinsic reactivities of acrylamides and contributeto large-scale predictive modeling and an understanding of the structure-activityrelationships of Michael acceptors for rational TCI design.

Automated summary

The electronic properties related to the carbanion intermediate were found to be strong predictors of glutathione reactivities of Michael acceptors. The & beta;-DMAM substitution was found to be cationic and enhance the charge accumulation at C-& alpha; upon carbanion formation.