Quantum Chemical Methods for Modeling Covalent Modification of Biological Thiols

Abstract

Targeted covalent inhibitor drugs require computational methods that go beyond simple molecular‐mechanical force fields in order to model the chemical reactions that occur when they bind to their targets. Here, several semiempirical and density‐functional theory (DFT) methods are assessed for their ability to describe the potential energy surface and reaction energies of the covalent modification of a thiol by an electrophile. Functionals such as PBE and B3LYP fail to predict a stable enolate intermediate. This is largely due to delocalization error, which spuriously stabilizes the prereaction complex, in which excess electron density is transferred from the thiolate to the electrophile. Functionals with a high‐exact exchange component, range‐separated DFT functionals, and variationally optimized exact exchange (i.e., the LC‐B05minV functional) correct this issue to various degrees. The large gradient behavior of the exchange enhancement factor is also found to significantly affect the results, leading to the improved performance of PBE0. While ωB97X‐D and M06‐2X were reasonably accurate, no method provided quantitative accuracy for all three electrophiles, making this a very strenuous test of functional performance. Additionally, one drawback of M06‐2X was that molecular dynamics (MD) simulations using this functional were only stable if a fine integration grid was used. The low‐cost semiempirical methods, PM3, AM1, and PM7, provide a qualitatively correct description of the reaction mechanism, although the energetics is not quantitatively reliable. As a proof of concept, the potential of mean force for the addition of methylthiolate to methylvinyl ketone was calculated using quantum mechanical/molecular mechanical MD in an explicit polarizable aqueous solvent. © 2019 Wiley Periodicals, Inc.

Mechanism of covalent binding of ibrutinib to Bruton's tyrosine kinase revealed by QM/MM calculations

“… 26 The 1,2-addition pathway, consisting of a direct PT from the thiol to the α-carbon of the acrylamide warhead and simultaneous S–C formation has been reported as a high energy pathway by Rowley et al who calculated the barrier of the 1,2-σ addition of methylvinyl ketone and methyl thiolate to be 65.2 kcal mol −1 at the CCSD(T)//ωB97X-D level. 27 QM/MM simulations of 1,2-addition in BTK suggested a very high barrier (approximately 47.7 kcal mol −1 ), and we therefore discounted it as a feasible mechanism based on our simulations and the findings of Rowley et al We also investigated the solvent-assisted variant of this pathway, but the free energy surface did not represent a feasible reaction pathway: we observed additional PTs that indicated a strong preference for the reaction to proceed via an enol intermediate (see ESI for details † ).…”

Systematic Study of the Glutathione Reactivity of N-Phenylacrylamides: 2. Effects of Acrylamide Substitution

“…Transition state optimization with the ωB97X-D functional was found to be significantly more reliable, and recently published work has shown that ωB97X-D is better suited to describing acrylamide reaction energetics relative to a CCSD(T) reference. 11 For these reasons, IEFPCM-ωB97X-D/6-311+G(d,p) was used for all calculations unless otherwise noted.…”

“…2-(Morpholinomethyl)-N-phenylacrylamide (11). Compound 11 was made according to the procedure for 10 using morpholine in place of dimethylamine.…”

A microscopic description of SARS-CoV-2 main protease inhibition with Michael acceptors. Strategies for improving inhibitor design

“…† This result conrms the adequacy of the B3LYP functional for the present Michael addition, in spite of the reported limitations of this functional to correctly describe some enolate or carbanion intermediates. 23,24 Note that these species are not strictly found in the proposed mechanism because of the proton transfer from His41 to the substrate. It must be also stressed that at both theoretical levels, the string converges to a mechanism evolving from the IP to the covalent product, conrming that, in agreement with our previous work, 10 the IP is a metastable species from which the most favorable mechanism may proceed.…”