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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Transcript of R OLE OF C YNLIN -D EPENDENT K INASES I NHIBITORS IN C ELL G ROWTH R EGULATION AND C ANCER...
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?
Cyclin-dependent kinases (CDKs) are a family of serine-threonine protein kinases.
WHAT IS CYCLIN?
WHICH ARE THE CYCLINS AND CDKS THAT INVOLVE IN CELL-
CYCLE PHASE?
WHAT IS CYCLIN-DEPENDENT KINASES INHIBITOR (CKI)?
TWO MAJOR CLASSES OF CKI FAMILY
WHAT IS THE MOLECULAR STRUCTURE OF P21?
•Six β -strands
•Five α-helices
CRYSTAL STRUCTURE OF P21
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.
THE MECHANISM OF P21 REGULATION
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.
WHAT DISEASE CAUSED BY POINT MUTATIONS IN P21 ?
LUNG CANCER
CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)
MYELOID LEUKEMIA
THYROID TUMOR
COLON TUMOR
ADENOCARCINOMA TUMOR OF THE PANCREAS
DRUG DESIGNS
2-ANILINO-4-(THIAZOL-5-YL) PYRIMIDINE (1PXN).
Ki = 0.07uM
Length =298
HOW DOES 1PXN BINDS TO THE PROTEIN?
1PXN bind to CDK2 at four ligands active site:
HYDROXYFASUDIL (2ERZ)
Ki=2.2uM
Length=351
HOW DOES 2ERZ BIND TO THE PROTEIN?
A B
1-(5-ISOQUINOLINESULFONYL)-2-METHYLPIPERAZINE (1YDR)
Ki=3uM
Length=350
HOW DOES 1YDR BIND THE PROTEIN?
BALANOL ANALOG 1 (1REJ)
Ki=3nMKi=5nM
Length =350
HOW DOES THE 1REJ BIND THE PROTEIN ?
STAUROSPORINE (1STC)
Ki=8nM
Length=350
HOW DOES 1STC BIND TO THE PROTEIN?
NU2058 (1H1P)
Ki=12uM
Length=303
HOW DOES 1H1P BIND TO THE PROTEIN?
HOW ARE EACH DRUG DIFFERENT FROM ONE ANOTHER?
EXPERIMENT
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.
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
THE
ENDTHANK YOU FOR
LISTENING
