JBJ-04-125-02 and AMP
Biochemical software.
Examples of calculated data obtained for
JBJ-04-125-02 and AMP
Examples of calculated data obtained for
JBJ-04-125-02 and AMP
Joint analysis of the effect of key mutations in the EGFR protein on binding to JBJ-04-125-02 and AMP
A mutant-selective EGFR allosteric inhibitor, JBJ-04-125-02, which as a single agent, can inhibit cell proliferation and EGFR L858R/T790M/C797S signaling in vitro and in vivo. However, increased EGFR dimer formation limits treatment efficacy and leads to drug resistance. Remarkably, osimertinib, an ATP-competitive covalent EGFR inhibitor, uniquely and significantly enhances the binding of JBJ-04-125-02 for mutant EGFR.[1]
Allosteric inhibition
Allosteric inhibition is a form of noncompetitive inhibition. This means that the inhibitor is not directly competing with the substrate at the active site. Instead, it is indirectly changing the composition of the enzyme. After changing its shape, the enzyme becomes inactive.
Direction of affinity change
A value lg(cond(W)) that shows the stability of a biological complex and shows the direction of change in the affinity of a dimer under various mutations.
Software that allows you to get preliminary results before conducting a laboratory experiment!
The compound JBJ-02–112-05, which has a 5-indole substituent appended to the isoindolinone moiety (Figure 1A), exhibited a biochemical potency of 15nM for L858R/T790M EGFR (Figure 1B).
Three-dimensional structure of the dimeric complex gefitinib-EGFR (PDB 3UG2 [28] a) and AMPPNP-EGFR (PDB: 3VJN) [33] b), small molecules gefitinib and AMPPNP compete for one binding site in the EGFR molecule [32]
Three-dimensional structure of the dimeric complex gefitinib-EGFR (PDB 3UG2 [28] a) and AMPPNP-EGFR (PDB: 3VJN) [33] b), small molecules gefitinib and AMPPNP compete for one binding site in the EGFR molecule [32]
Results of numerical modeling of substitutions of amino acid residues in the EGFR protein.
For convenience, the graphs indicate the corresponding experimental results obtained.
The higher lg(cond(W)) value, the worse the affinity of the dimeric complex. Results of numerical calculations of the dependence of the lg(cond (W)) value on the substitution of amino acid residue in EGFR upon binding to AMPPNP a) and gefitinibe b)
The higher lg(cond(W)) value, the worse the affinity of the dimeric complex. Results of numerical calculations of the dependence of the lg(cond (W)) value on the substitution of amino acid residue in EGFR upon binding to AMPPNP a) and gefitinibe b)
Results
obtained numerical calculations on the effect of mutations in the EGFR protein on the binding affinity to two competing molecules Gefitinib and AMP-PNP
1. Results of numerical simulations, we found that an additional mutation L858R to T790M significantly enhances ATP-binding affinity of the L858R mutant
2. Numerical modeling revealed that the introduction of mutations T790M and L858R / T790M are characterized by a higher affinity for ATPPMP than an increase in the affinity for gefitinib. The increased ATP affinity of the L858R / T790M mutant leads to gefitinib resistance at cellular concentrations of ATP
3. Results of numerical simulations showed the T790M mutation binds gefitinib with a higher affinity than wild-type EGFR.
4. Results of numerical simulations showed the L858R substitution is also characterized by a higher affinity for gefitinib than the wild-type protein.
5. Results of numerical simulations showed substitution G719 has a higher affinity for gefitinib than for wild-type protein.
6. Results of numerical simulations showed substitution of G719S / T790M results in a higher affinity for both gefitinib and AMAPNP.
7. Numerical analysis of the two substitutions G719S and G719S / T790M indicates that the double mutation G719S / T790M results in a greater affinity for gefitinib.
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. Application of our method will allow you to identify mutations that lead to a decrease in the affinity of components. 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.
Biochemical | biological software.
Software that allows you to get preliminary results before conducting a laboratory experiment!
Benefits of using our software for various biochemical studies:
Benefits of using our software for various biochemical studies:
