Examples of calculated data obtained
for CO-1686

Biochemical software

Results of numerical calculations of the effect of amino acid residue substitutions in EGFR on binding to Rociletinib (CO-1686)

Rociletinib (CO-1686) is an irreversible, mutant-selective EGFR inhibitor[52]. It is a medication developed to treat non-small cell lung carcinomas with a specific mutation. It is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor. It was being developed by Clovis Oncology as a potential treatment for non-small-cell lung cancer [53]

Three-dimensional structure of CO-1686-EGFR dimer with indication of key amino acid residues (PDB 5XDL [43])

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Software that allows you to get preliminary results before conducting a laboratory experiment!
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.
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Software Data Results

The results of numerical calculations of two different structures (5XDK and 5XDL) EGFR-Rociletinib (CO-1686) are in good agreement.
1. Substitution of L844V leads to a decrease in the stability of the mEGFR (L844V) - Rociletinib dimeric complex when analyzing the 5XDK and 5XDL sutures (the difference in the cond (W) value between the two mEGFR (L844V) - Rociletinib and wtEGFR-Rociletinib complexes was 300)

2. Replacement of T790M leads to increased resistance of mEGFR (T790M) - Rociletinib

3. Double substitution of T790M / L858R leads to a significant increase in the stability of the mEGFR dimer (T790M / L858R) - Rociletinib. Numerical calculations of the two structures showed similar results.

4. Replacement of L858R led to an increase in the stability of the mEGFR complex (L858R) - Rociletinib

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

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