biostudies-literatureChaudhuri SWellcome LeapDepartment for Science, Innovation and TechnologyRoyal Academy of EngineeringWellcome TrustEngineering and Physical Sciences Research Council7687-7697https://www.ebi.ac.uk/biostudies/studies/S-EPMC11480980biostudies-literatureUnknown64(19)Myotonic dystrophy type I (DM1) is the most common form of adult muscular dystrophy and is a severe condition with no treatment currently available. Recently, small-molecule ligands have been developed as targeted covalent inhibitors that have some selectivity for and covalently inhibit cyclin-dependent kinase 12 (CDK12). CDK12 is involved in the transcription of elongated RNA sections that results in the DM1 condition. The covalent bond is achieved after nucleophilic addition to a Michael acceptor warhead. Previous studies of the conformational preferences of thio-Michael additions have focused on characterizing the reaction profile based on the distance between the sulfur and β-carbon atoms. Rotamerism, however, has not been investigated extensively. Here, we use high-level quantum chemiJournal of chemical information and modelingQuantum Chemical Characterization of Rotamerism in Thio-Michael Additions for Targeted Covalent Inhibitors.PMC11480980CiET2021_17Q4Bio-2023-4424538316EP/W028131/1Hayes CJChaudhuri SRogers DMHirst JDInzani KfalseQuantum Chemical Characterization of Rotamerism in Thio-Michael Additions for Targeted Covalent Inhibitors.Myotonic dystrophy type I (DM1) is the most common form of adult muscular dystrophy and is a severe condition with no treatment currently available. Recently, small-molecule ligands have been developed as targeted covalent inhibitors that have some selectivity for and covalently inhibit cyclin-dependent kinase 12 (CDK12). CDK12 is involved in the transcription of elongated RNA sections that results in the DM1 condition. The covalent bond is achieved after nucleophilic addition to a Michael acceptor warhead. Previous studies of the conformational preferences of thio-Michael additions have focused on characterizing the reaction profile based on the distance between the sulfur and β-carbon atoms. Rotamerism, however, has not been investigated extensively. Here, we use high-level quantum chemi2024-01-01T00:00:00Z2024 Oct2025-04-04T07:40:45.766Z2025-04-04T07:40:45.766ZS-EPMC114809803926506810.1021/acs.jcim.4c01379