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Role of Cynlin -Dependent Kinases Inhibitors in Cell Growth Regulation and Cancer

Role of Cynlin -Dependent Kinases Inhibitors in Cell Growth Regulation and Cancer. Thanh-Binh Nancy Le. Overview. First: Introduce the Biological Review Second: Review the Drug Design Third: Demonstrate the Experiment. BIOLOGICAL REVIEW . What is Cyclin -Dependent Kinases ?.

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Role of Cynlin -Dependent Kinases Inhibitors in Cell Growth Regulation and Cancer

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  1. Role of Cynlin-Dependent Kinases Inhibitors in Cell Growth Regulation and Cancer Thanh-Binh Nancy Le

  2. Overview First: Introduce the Biological Review Second: Review the Drug Design Third: Demonstrate the Experiment

  3. BIOLOGICAL REVIEW

  4. What is Cyclin-Dependent Kinases? • Cyclin-dependent kinases (CDKs) are a family of serine-threonine protein kinases.

  5. What is Cyclin?

  6. which are the cyclins and CDKs that involve in cell-cycle phase?

  7. what is cyclin-dependent kinases inhibitor (CKI)?

  8. Two major classes of CKI family

  9. what is the molecular structure of p21? • Six β -strands • Five α-helices

  10. Crystal Structure of p21

  11. what is the function of p21 in cell cycle regulation? • Control and consequent loss of cell cycle checkpoints. • Stop cell cycle to induce differentiation and senescence.

  12. the mechanism of p21 regulation

  13. What will happen if p21 is mutated? • Oncogenic mutation. • Higher barrier for conformational change. • Not undergo conformational change. • Rearrange Loop 4 • Increase the lifetime of the active state. • Results in continuation of signal for cell growth.

  14. What Disease caused by point mutations in p21 ?

  15. Lung cancer

  16. Chronic Obstructive pulmonary disease (COPD)

  17. Myeloid leukemia

  18. Thyroid tumor

  19. COLON TUMOR

  20. Adenocarcinoma tumor of the pancreas

  21. Drug Designs

  22. 2-Anilino-4-(thiazol-5-yl) pyrimidine(1pxn). Ki = 0.07uM Length =298

  23. How does 1PXN binds to the protein? • 1PXN bind to CDK2 at four ligands active site:

  24. hydroxyfasudil (2ERZ) Ki=2.2uM Length=351

  25. How does 2ERZ bind to the protein? A B

  26. 1-(5-ISOQUINOLINESULFONYL)-2-METHYLPIPERAZINE (1YDR) Ki=3uM Length=350

  27. How does 1YDR bind the protein?

  28. balanol analog 1 (1REJ) Ki=5nM Ki=3nM Length =350

  29. How does the 1REJ bind the protein ?

  30. STAUROSPORINE (1STC) Ki=8nM Length=350

  31. How does 1stc bind to the protein?

  32. NU2058 (1H1P) Ki=12uM Length=303

  33. How does 1h1p bind to the protein?

  34. How are each drug different from one another?

  35. EXPERIMENT

  36. Purpose of the Lab Understand Competitive binding of the Cyclin-Kinase Inhibitors CDK2 over the substrate. How different functional groups in the inhibitors play the inhibitor binding.

  37. Method • Get CDK2 protein from pdb bank. • Creatingprmtop files • Create t-leap • Calculate the relative binding affinities of CDK inhibitors. • Using MM-PBSA in the Amber software

  38. THEEND THANK YOU FOR LISTENING 

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