Quantum Chemical\nCharacterization of Rotamerism in\nThio-Michael Additions for Targeted Covalent Inhibitors

Myotonic dystrophy type I (DM1) is the most common form\nof adult\nmuscular dystrophy and is a severe condition with no treatment currently\navailable. Recently, small-molecule ligands have been developed as\ntargeted covalent inhibitors that have some selectivity for and covalently\ninhibit cyclin-dependent kinase 12 (CDK12). CDK12 is involved in the\ntranscription of elongated RNA sections that results in the DM1 condition.\nThe covalent bond is achieved after nucleophilic addition to a Michael\nacceptor warhead. Previous studies of the conformational preferences\nof thio-Michael additions have focused on characterizing the reaction\nprofile based on the distance between the sulfur and β-carbon\natoms. Rotamerism, however, has not been investigated extensively.\nHere, we use high-level quantum chemistry calculations, up to coupled\ncluster with single, double, and perturbative triple excitations [CCSD(T)],\nto characterize the nucleophilic addition of an archetypal nucleophile,\nmethanethiolate, to various nitrogen-containing Michael acceptors\nwhich are representative of the small-molecule covalent inhibitors.\nBy investigating the structural, energetic, and electronic properties\nof the resulting enolates, as well as their reaction profiles, we\nshow that synclinal additions are generally energetically favored\nover other additions due to the greater magnitude of attractive noncovalent\ninteractions permitted by the conformation. The calculated transition\nstates associated with the addition process indicate that synclinal\naddition proceeds via lower energetic barriers than antiperiplanar\naddition and is the preferred reaction pathway.