Computational Study of the Addition of Methanethiol to 40+ Michael Acceptors as a Model for the Bioconjugation of Cysteines.

ABSTRACT: A long series of Michael acceptors are studied computationally as potential alternatives to the maleimides that are used in most antibody-drug conjugates to link Cys of mAbs with cytotoxic drugs. The products of the reaction of methanethiol (CH₃SH/MeSH, as a simple model of Cys) with N-methylated ethynesulfonamide, 2-ethynylpyridinium ion, propynamide, and methyl ethynephosphonamidate (that is, with HC≡C-EWG) are predicted by the M06-2X/6-311+G(d,p) method to be thermodynamically more stable, in relation to their precursors, than that of MeSH with N-methylmaleimide and, in general, with H₂C═CH-EWG; calculations with AcCysOMe and ^tBuSH are also included. However, for the addition of the anion (MeS^-), which is the reactive species, th

SUBMITTER: Costa AM 

PROVIDER: S-EPMC8631706 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature