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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)-2METHYLPIPERAZINE (1YDR)
Ki=3uM
Length=35
0
HOW DOES 1YDR BIND THE
PROTEIN?
BALANOL ANALOG
1 (1REJ)
Ki=5nM
Ki=3nM
Length =350
HOW DOES THE 1REJ BIND THE
PROTEIN ?
STAUROSPORINE (1STC)
Ki=8nM
Length=35
0
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?
EXPERIMEN
T
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
END
THANK YOU FOR
LISTENING 
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