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Updated: Jun 13, 2025
06:17
Covalent Fragment Screening Using the Quantitative Irreversible Tethering Assay
Published on: February 28, 2025
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Quantum Chemical Characterization of Rotamerism in Thio-Michael Additions for Targeted Covalent Inhibitors
Shayantan Chaudhuri1, David M Rogers1, Christopher J Hayes1
1School of Chemistry, University of Nottingham, Nottingham NG7 2RD, U.K.
Journal of Chemical Information and Modeling
|September 12, 2024
Summary
Targeted covalent inhibitors targeting cyclin-dependent kinase 12 (CDK12) show promise for treating myotonic dystrophy type I (DM1). Quantum chemistry calculations reveal synclinal addition is the preferred pathway for inhibitor development.
Area of Science:
- Medicinal Chemistry
- Computational Chemistry
- Molecular Biology
Background:
- Myotonic dystrophy type I (DM1) is a severe adult muscular dystrophy with no current treatments.
- Small-molecule ligands targeting cyclin-dependent kinase 12 (CDK12) are being developed as covalent inhibitors for DM1.
- CDK12 inhibition is crucial as it regulates the transcription of elongated RNA implicated in DM1.
Purpose of the Study:
- To investigate the rotamerism and conformational preferences of thio-Michael additions in the context of CDK12 inhibitor development.
- To characterize the nucleophilic addition of methanethiolate to nitrogen-containing Michael acceptors using high-level quantum chemistry.
- To determine the energetically favored reaction pathway for covalent inhibitor formation.
Main Methods:
- High-level quantum chemistry calculations, including coupled cluster with single, double, and perturbative triple excitations [CCSD(T)].
- Analysis of structural, energetic, and electronic properties of resulting enolates.
- Characterization of reaction profiles and transition states for nucleophilic addition.
Main Results:
- Synclinal additions were found to be energetically favored over other conformations.
- Attractive noncovalent interactions play a significant role in stabilizing synclinal additions.
- Calculated transition states showed lower energetic barriers for synclinal addition compared to antiperiplanar addition.
Conclusions:
- Synclinal addition represents the preferred reaction pathway for the development of CDK12-targeted covalent inhibitors.
- Understanding rotamerism is critical for optimizing the design of small-molecule inhibitors for DM1.
- These findings provide valuable insights for the rational design of effective DM1 therapeutics.
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