Covalent-modifier drugs act on their target by forming a chemical bond with a side-chain of the targeted protein. These covalent modifiers account for 26% of enzyme-targeting drugs, including widely used drugs such as penicillin and aspirin. Recently, this mode of action has been used to develop a new class of anti-cancer drugs that contain an electrophilic group that forms a chemical bond with the target kinase.
Modeling the activity of these inhibitors requires a more sophisticated set of simulation tools than the tools that are used to model conventional reversible-binding drugs. These include pKa calculations to determine which amino acids are the most reactive and QM/MM simulations to model the chemical reaction between the drug and its target. We are currently studying the kinase family of proteins, which contain many important targets for anti-cancer drugs. Covalent-modifier drugs have the potential to improve the selectivity for target kinases.
Awoonor-Williams, E., Walsh, A. G., Rowley, C. N. Modeling Covalent-Modifier Drugs, BBA Proteins and Proteom. 2017, Invited review, doi: 10.1016/j.bbapap.2017.05.009
Smith, J. M., Rowley, C.N. Automated computational screening of the thiol reactivity of substituted alkenes. J. Comput. Aided Mol. Des. 2015, doi: 10.1007/s10822-015-9857-0
Smith, J. M., Jami Alahmadi, Y., Rowley, C.N. Range-Separated DFT Functionals are Necessary to Model Thio-Michael Additions. J. Chem. Theory Comput. 2013, 9 (11), 4860
A review of irreversible inhibitors in medicinal chemistry: Potashman, M. H.; Duggan, M. E. Covalent Modifiers: An Orthogonal Approach to Drug Design. J. Med. Chem. 2009, 52, 1231