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Hagar Tadmor
Computational Tools Seminar
 PI3K/Akt signaling pathway
 Research aim & rationale
 Methods
 Results
 Conclusions & Future thoughts
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PI3K/mTOR & the Akt signaling pathway (1)
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PI3K/mTOR & the Akt signaling pathway (2)
4
Research aim & rationale
PI3K and mTOR share a high structure similarity at their
catalytic sites. Therefore, a drug with dual inhibition activity
for both PI3K and mTOR may be developed to shut down
Akt activation.
To investigate the molecular basis of the inhibition against
PI3K/mTOR
To identify the structure features of the compounds with
morpholino-triazine scaffold that primarily contribute to the
inhibition of PI3K/mTOR.
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Methods (1)
Activities (IC50) of bis (morpholino-1,3,5-triazine)
derivatives for PI3Ka and mTOR were retrieved from
PubChem Assay
X 5
+
MAC most active compound
LAC least active compound
PKI-587
Pharmacophore Modeling
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abstract description of molecular features
Methods (2)
3D-QSAR
Quantitative structure–activity relationship
Protein-Ligand Docking
Computational methods for the prediction
of ligand-protein structural information
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Results (1) - Pharmacophore model
MAC of PI3Ka.
Pink: HB acceptor
light blue: HB donor
purple: positive feature
orange ring: aromatic ring
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Results (2) - SAR-table
Structure
name
R1
R2
Core
number
IC50 PI3k IC50 mTOR
44473371
1
9.40
9.30
45379226
1
9.40
9.22
44546953
1
9.40
8.80
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Results (3)-Observed and predicted
activities
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PI3k
mTOR
CID
observed
predicted
observed
predicted
44473371
9.40a
9.66
9.30a
9.30
45379226
9.40a
9.41
9.22
8.93
44546953
9.40a
9.27
8.80
8.68
Results (4)-PI3Kα-MAC Interactions
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Results(5)-mTOR-MAC Interactions
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Results (6)-Ligand interaction diagram -PI3Kα
in docked complex structure for the MAC(A)
and LAC(B)
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Results (7)-Ligand interaction diagram mTOR in docked complex structure for the
MAC(A) and the LAC(B)
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Results (8)-Ligand interaction diagram
showing residues near PKI-587 in docked
complex structure PI3k (A), Mtor (B)
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Conclusions & Future thoughts
MACs for PI3Ka and mTOR shared the same
mechanism of the inhibition as suggested by the
QSAR model and docking study.
MAC and
amine on
- might
inhibition
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LAC differed by one HB formed with
the one end of the ligand molecule.
be a key principle for achieving dual
bioactivity.
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