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

Abstract

Predictive modeling and understanding of chemical warhead reactivities have the potential to accelerate targeted covalent drug discovery. Recently, the carbanion formation free energies as well as other ground-state electronic properties from density functional theory (DFT) calculations have been proposed as predictors of glutathione reactivities of Michael acceptors; however, no clear consensus exists. By profiling the thiol-Michael reactions of a diverse set of singly- and doubly-activated olefins, including several model warheads related to afatinib, here we reexamined the question of whether low-cost electronic properties can be used as predictors of reaction barriers. The electronic properties related to the carbanion intermediate were found to be strong predictors, e.g., the change in the Cβ charge accompanying carbanion formation. The least expensive reactant-only properties, the electrophilicity index, and the Cβ charge also show strong rank correlations, suggesting their utility as quantum descriptors. A second objective of the work is to clarify the effect of the β-dimethylaminomethyl (DMAM) substitution, which is incorporated in the warheads of several FDA-approved covalent drugs. Our data suggest that the β-DMAM substitution is cationic at neutral pH in solution and promotes acrylamide’s intrinsic reactivity by enhancing the charge accumulation at Cα upon carbanion formation. In contrast, the inductive effect of the β-trimethylaminomethyl substitution is diminished due to steric hindrance. Together, these results reconcile the current views of the intrinsic reactivities of acrylamides and contribute to large-scale predictive modeling and an understanding of the structure–activity relationships of Michael acceptors for rational TCI design.

QM/MM simulations of EFGR with afatinib reveal the role of theβ-dimethylaminomethyl substitution

“…The calculated free energy profiles showed that in either mechanism, the reaction follows a classical Michael addition, which involves a stable intermediate and the nucleophilic attack as the rate-limiting step. The Michael addition mechanism of afatinib in EGFR is consistent with the solution chemistry experiments 4,6,8 and QM calculations 7,15,19 as well as the recent DFT QM/MM simulations of the reaction of ibrutinib with the BTK kinase. 21 However, the Michael addition mechanism of afatinib does not support the concerted mechanism concluded from the earlier semiempirical DFTB QM/MM simulations of the reactions of 13-JAB and osimertinib with EGFR.…”

“…The PDDG-PM3 calculated heats of formation of model compounds methanethiol, methylthiolate, and acrylamide (CH 2 − − CHCONH 2 ) are in good agreement with experimental data (Table S5). We also compared the model reaction enthalpies calculated by the PDDG-PM3 method and the long-range corrected meta-GGA DFT method ωB97X-D3BJ, 34,35 which was used in our previous work on the solution reactivities of model acrylamide warheads 19 (Table S2). PDDG-PM3 calculations were performed using CHARMM; 36 ωB97X-D3BJ calculations were performed using the ORCA package (version 5.1.1).…”

“…This direct (i.e., non-Michael) mechanism is in contradiction with the solution chemistry experiments [4][5][6]8 and QM calculations of the thiol additions of various activated olefins. 7,[15][16][17][18][19] More recently, two QM/MM studies 20,21 examined the reaction mechanism of the acrylamide TCIs with the front-pocket cysteine Cys481 in BTK, which was found to be deprotonated in the CpHMD simulations. 10 The QM/MM simulations employing the density functional theory (DFT) QM description of a truncated α-cyano acrylamide inhibitor and starting from a deprotonated Cys797 confirmed the Michael reaction mechanism involving an intermediate.…”

“…stituent, implying that a positively charged β substitution increases the Michael reaction rate. To explain this, our recent QM calculations of model reactions in solution (implicit solvent model) 19 found that a charged β-DMAM group lowers the reaction barrier of nucleophilic attack. However, in the protein environment, the reaction mechanism of β-DMAM substituted inhibitors may be different from that in solution, especially in the presence of a protonated cysteine.…”

A robust computational quest: Discovering potential hits to improve the treatment of pyrazinamide‐resistant Mycobacterium tuberculosis

“…65 Liu et al validated the use of quantum descriptors in predicting and understanding the reactivity of covalent warheads associated with afatinib and demonstrated their utility in developing covalent inhibitors. 66 The integration of Artificial Intelligence in Drug Design (AIDD)…”