Examples of calculated data obtained for Gefitinib and AMP

Biochemical software

Joint analysis of the effect of key mutations in the EGFR protein on binding to Gefitinib and AMP

Gefitinib (Iressa) is an orally active TK inhibitor
(TKI) that blocks signal transduction pathways implicated
in cancers. The structures of the L858R and G719S mutants
complexed with either AMPPNP or the inhibitors,
gefitinib and AEE788, revealed that the overall conformation
and ligand-binding modes are very similar to
those of the wild-type EGFR-TK in the active
conformation
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.
chemical structure, chemical structure of water, chemical bonding and molecular structure class, chemical formula of water
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]
The tyrosine kinase inhibitor gefitinib inhibits mutated EGFR and is registered for treatment of NSCLC. Gefitinib is active in patients who have mutations in the EGFR kinase domain and to a lesser extent EGFR amplification, which corresponds with 10% of the patient group [46] [47] [48].

Specifically, this agent competes with the binding of ATP to the tyrosine kinase domain of EGFR, thereby inhibiting receptor autophosphorylation and resulting in inhibition of signal transduction[ 49].

Gefitinib (Iressa) is an orally active TK inhibitor (TKI) that blocks signal transduction pathways implicated in cancers. The structures of the L858R and G719S mutants complexed with either AMPPNP or the inhibitors, gefitinib and AEE788, revealed that the overall conformation and ligand-binding modes are very similar to those of the wild-type EGFR-TK in the active conformation[ 50]. The T790M mutation of EGFR increases the ATP affinity of the G719S mutant, explaining the acquired drug resistance of the double mutant[ 35]. Structural analyses of the G719S/T790M double mutant, as well as the wild type and the G719S and L858R mutants, revealed that the T790M mutation stabilizes the hydrophobic spine of the active EGFR-TK conformation [ 35]. Determined the IC50 (half maximal inhibitory concentration) value of the G719S/T790M double mutant EGFR-TK domain and compared its gefitinib sensitivity with those of the wild-type and G719S mutant proteins [35].

Software that allows you to get preliminary results before conducting a laboratory experiment!
chemical structure, chemical structure of water, chemical bonding and molecular structure class, chemical formula of water
Data on the calculation of the conformational mobility of small molecules
metastatic breast cancer, breast cancer, colon cancer, what is colon cancer, pfizer oncology together,
Plots of Kd change depending on mutation in EGFR Inhibitor dissociation constants for the WT and mutant EGFR kinases [51] a) and IC50 depending on mutation in EGFR protein. [35]

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)

metastatic breast cancer, breast cancer, colon cancer, what is colon cancer, pfizer oncology together,

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.

Examples using small molecules are given below

List of Literatures

1. What are the drugs of the future?

2. A big future for small molecules: targeting the undruggable

3. Small-Molecule Drug Development: Advantages of an Integrated, Phase-Based Approach

4. https://www.marketwatch.com/press-release/small-molecule-drug-discovery-market-trend-survey-2021-with-top-countries-data-industry-growth-size-share-forecasts-analysis-company-profiles-competitive-landscape-and-key-regions-analysis-research-report-with-covid-19-analysis-2021-03-08

5. https://www.malvernpanalytical.com/en/products/measurement-type/binding-affinity

6. . Determination of half-maximal inhibitory concentration using biosensor-based protein interaction analysis

7. Titration ELISA as a Method to Determine the Dissociation Constant of Receptor Ligand Interaction

8. Differential binding of human immunoagents and Herceptin to the ErbB2 receptor

9. Using Electrophoretic Mobility shift Assays to Measure Equilibrium Dissociation Constants: GAL4-p53 Binding DNA as a Model System

10. Quantitative analysis of protein-RNA interactions by gel mobility shift equilibrium dialysis.

11. Determination of the Binding Parameters of Drug to Protein by Equilibrium Dialysis/Piezoelectric Quartz Crystal Sensor

12. Analytical Ultracentrifugation as a Tool to Study Nonspecific Protein–DNA Interactions

13. Use of Surface Plasmon Resonance (SPR) to Determine Binding Affinities and Kinetic Parameters Between Components Important in Fusion Machinery]

14. Structure of CD20 in complex with the therapeutic monoclonal antibody rituximab]

15. Fluorescence Titrations to Determine the Binding Affinity of Cyclic Nucleotides to SthK Ion Channels],

16. DNA binding to alkaloids

17. Determination of equilibrium dissociation constants for recombinant antibodies by high-throughput affinity electrophoresis

18. Transformation of Low-Affinity Lead Compounds into High-Affinity Protein Capture Agents

19. Predicting the Impact of Missense Mutations on Protein–Protein Binding Affinity

20. Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways

21. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib

22. Advances in studies of tyrosine kinase inhibitors and their acquired resistance

23. Structural insight into the binding mechanism of ATP to EGFR and L858R, and T790M and L858R/T790 mutants

24. Efficacy of rociletinib (CO-1686) in plasma-genotyped T790M-positive non-small cell lung cancer (NSCLC) patients (pts)

25. Synthesis and Fundamental Evaluation of Radioiodinated Rociletinib (CO-1686) as a Probe to Lung Cancer with L858R/T790M Mutations of Epidermal Growth Factor Receptor (EGFR

26. Pharmacological and Structural Characterizations of Naquotinib, a Novel Third-Generation EGFR Tyrosine Kinase Inhibitor, in EGFR-Mutated Non-Small Cell Lung Cancer

27. Structural Basis for the Regulation of PPARγ Activity by Imatinib

28. PDB https://www.rcsb.org/structure/3UG2

29. Матанство

30. https://pubchem.ncbi.nlm.nih.gov/compound/Water

31. https://pubchem.ncbi.nlm.nih.gov/compound/1%2C4-butanediol

32. https://pubchem.ncbi.nlm.nih.gov/compound/Gefitinib

33. https://www.rcsb.org/structure/3VJN

34. Nonhydrolyzable ATP analog 5'-adenylyl-imidodiphosphate (AMP-PNP) does not inhibit ATP-dependent scanning of leader sequence of mRNA

35. Structural basis for the altered drug sensitivities of non-small cell lung cancer-associated mutants of human epidermal growth factor receptor

36. https://www.rcsb.org/structure/5XDK

37. Structural basis of mutant-selectivity and drug-resistance related to CO-1686

38. https://www.selleckchem.com/products/co-1686.html

39. https://www.rcsb.org/structure/6KTN

40. Structural Basis for the Regulation of PPARγ Activity by Imatinib

41. Small Molecule Kinase Inhibitors as Anti-Cancer Therapeutics

42. Influence of chemotherapy on EGFR mutation status

43. https://www.rcsb.org/structure/5XDL

44. https://www.rcsb.org/structure/5Y9T

45. https://www.rcsb.org/structure/1M17

46. Tyrosine kinase inhibitors: Multi-targeted or single-targeted?

47. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib

48. Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials

49. Advances in studies of tyrosine kinase inhibitors

50. Structures of lung cancer-derived EGFR mutants and inhibitor complexes: Mechanism of activation and insights into differential inhibitor sensitivity

51. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP

52. Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC

53. New developments in the management of non-small-cell lung cancer, focus on rociletinib: what went wrong

54. Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC

55. Tjin Tham Sjin R, Lee K, Walter AO, Dubrovskiy A, SheetsM, Martin TS, Labenski MT, Zhu Z, Tester R, Karp R,Medikonda A, Chaturvedi P, Ren Y, et al. In vitro and in vivo characterization of irreversible mutant-selective EGFR inhibitors that are wild-type sparing. Mol Cancer Ther. 2014; 13:1468-1479.]

56. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury

57. Yki-Jarvinen H. Thiazolidinediones. N Engl J Med (2004) 351:1106–18. doi:10.1056/NEJMra041001

58. PPAR-γ Agonists As Antineoplastic Agents in Cancers with Dysregulated

59. Novel Third-Generation EGFR Tyrosine Kinase Inhibitors and Strategies to Overcome Therapeutic Resistance

60. Markedly increased ocular side effect causing severe vision deterioration after chemotherapy using new or investigational

.
Made on
Tilda