The numerical results correspond well to the previously obtained IC50 values; namely, the L858R substitutions in EGFR lead to a decrease in the two values of IC50 and lg(cond(W)) when interacting with erlotinib. The double substitution of T790M/L858R in EGFR leads to an increase in the experimental and calculated values of IC50 and lg(cond(W)). At the same time, we interpret the increase in lg(cond(W)), when the system switches from the wild-type to a mutant form of mEGFR (T790M/L858R)-erlotinib as a decrease in dimer stability which is reflected in the decrease in the affinity of the mutant form of the protein to erlotinib.
The experimental values were taken [In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer]
1. Thus, the numerical method developed by us makes it possible to determine the range of changes in the stability of dimeric complexes with the participation of a small chemical molecule and a protein molecule.
2. Application of our method will allow us to identify mutations that lead to a decrease in the affinity of components.
3. Numerical analysis requires a three-dimensional structure of the dimer under study, in the protein component of which substitutions of amino acid residues will be introduced.