R OLE OF C YNLIN -D EPENDENT K INASES I NHIBITORS IN C ELL G ROWTH R EGULATION AND C ANCER...
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Transcript of R OLE OF C YNLIN -D EPENDENT K INASES I NHIBITORS IN C ELL G ROWTH R EGULATION AND C ANCER...
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ROLE OF CYNLIN-DEPENDENT KINASES INHIBITORS IN CELL
GROWTH REGULATION AND CANCER
Thanh-Binh Nancy Le
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OVERVIEW
First: Introduce the Biological Review
Second: Review the Drug Design
Third: Demonstrate the Experiment
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BIOLOGICAL REVIEW
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WHAT IS CYCLIN-DEPENDENT KINASES?
Cyclin-dependent kinases (CDKs) are a family of serine-threonine protein kinases.
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WHAT IS CYCLIN?
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WHICH ARE THE CYCLINS AND CDKS THAT INVOLVE IN CELL-
CYCLE PHASE?
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WHAT IS CYCLIN-DEPENDENT KINASES INHIBITOR (CKI)?
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TWO MAJOR CLASSES OF CKI FAMILY
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WHAT IS THE MOLECULAR STRUCTURE OF P21?
•Six β -strands
•Five α-helices
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CRYSTAL STRUCTURE OF P21
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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.
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THE MECHANISM OF P21 REGULATION
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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.
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WHAT DISEASE CAUSED BY POINT MUTATIONS IN P21 ?
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LUNG CANCER
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CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)
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MYELOID LEUKEMIA
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THYROID TUMOR
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COLON TUMOR
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ADENOCARCINOMA TUMOR OF THE PANCREAS
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DRUG DESIGNS
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2-ANILINO-4-(THIAZOL-5-YL) PYRIMIDINE (1PXN).
Ki = 0.07uM
Length =298
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HOW DOES 1PXN BINDS TO THE PROTEIN?
1PXN bind to CDK2 at four ligands active site:
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HYDROXYFASUDIL (2ERZ)
Ki=2.2uM
Length=351
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HOW DOES 2ERZ BIND TO THE PROTEIN?
A B
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1-(5-ISOQUINOLINESULFONYL)-2-METHYLPIPERAZINE (1YDR)
Ki=3uM
Length=350
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HOW DOES 1YDR BIND THE PROTEIN?
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BALANOL ANALOG 1 (1REJ)
Ki=3nMKi=5nM
Length =350
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HOW DOES THE 1REJ BIND THE PROTEIN ?
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STAUROSPORINE (1STC)
Ki=8nM
Length=350
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HOW DOES 1STC BIND TO THE PROTEIN?
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NU2058 (1H1P)
Ki=12uM
Length=303
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HOW DOES 1H1P BIND TO THE PROTEIN?
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HOW ARE EACH DRUG DIFFERENT FROM ONE ANOTHER?
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EXPERIMENT
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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.
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METHOD• Get CDK2 protein from pdb bank.• Creating prmtop files • Create t-leap• Calculate the relative binding
affinities of CDK inhibitors.• Using MM-PBSA in the Amber
software
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THE
ENDTHANK YOU FOR
LISTENING