Figure 2. Chemical structures of Erlotinib-EGFR dimer with indication of key amino acid residues
Figure 3.Results of numerical calculations and comparison with the obtained experimental data.
The first graph (red) shows the dependence of the value IC50 on the mutation in the EGFR protein, the second and third graphs (blue) shows the results of the calculations using the software developed by us, which shows the direction of the change in affinity for mutations in proteins
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.
9.056660e-19 7.560563e-09 7.561525e-09
Norm of step
Finding the minimum of constrained nonlinearmultivariable function
From table follow value local minimum (fmin = 7.561525e-09) and so, structure PDB:1M17 is formed correctly. If an optimized cost function for a specific PDB structure is not found, then we consider that this structure is formed incorrectly (see fig. 1)
The fig.1 shows a rapidly oscillating character, which indicates the impossibility of finding a local minimum: optimization completed because at the initial point, the objective function is non-decreasing in feasible directions.
Figure 1: Dependence of RMSD(root-mean-square deviation) on the configuration number
error computational SVD
error computational SVD
impossibility of finding a local minimum
Determination of the computational error of the SVD
Dependence of RMSD(root-mean-square deviation) on the configuration number.
4. Comparison of calculated data of two structures 1M17 and 4HJO.
5. Comparison of experimental and calculated data.
The value local minimum is fmin = 7.561525e-09 so structure PDB:1M17 is formed correctly
A local minimum wasn't found.
error computational SVD 1.189e-34
error computational SVD 2.219e-34
EGFR tyrosine kinase domain with inhibitor erlotinib
EGFR tyrosine kinase domain with 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]