1. Computational Tools Seminar
Hagar Tadmor
Computational Tools Seminar

2. PI3K/Akt signaling pathway
Research aim & rationale
Methods
Results
Conclusions & Future thoughts

3. PI3K/mTOR & the Akt signaling pathway (1)

4. PI3K/mTOR & the Akt signaling pathway (2)

5. 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.

6. Methods (1) + MAC most active compound LAC least active compound X 5
Activities (IC50) of bis (morpholino-1,3,5-triazine) derivatives for PI3Ka and mTOR were retrieved from PubChem Assay
MAC most active compound
LAC least active compound
PKI-587
X 5 +
Pharmacophore Modeling
abstract description of molecular features

7. Protein-Ligand Docking
Methods (2)
3D-QSAR
Quantitative structure–activity relationship
Protein-Ligand Docking
Computational methods for the prediction of ligand-protein structural information

8. Results (1) - Pharmacophore model
MAC of PI3Ka.
Pink: HB acceptor
light blue: HB donor
purple: positive feature
orange ring: aromatic ring

9. Results (2) - SAR-table IC50 mTOR IC50 PI3k Core number R2 R1
Structure name
9.30
9.40 1
9.22
8.80

10. Results (3)-Observed and predicted activities
mTOR
PI3k
CID
predicted
observed
9.30
9.30a
9.66
9.40a
8.93
9.22
9.41
8.68
8.80
9.27

11. Results (4)-PI3Kα-MAC Interactions

12. Results(5)-mTOR-MAC Interactions

13. Results (6)-Ligand interaction diagram -PI3Kα in docked complex structure for the MAC(A) and LAC(B)

14. Results (7)-Ligand interaction diagram - mTOR in docked complex structure for the MAC(A) and the LAC(B)

15. Results (8)-Ligand interaction diagram showing residues near PKI-587 in docked complex structure PI3k (A), Mtor (B)

16. 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 LAC differed by one HB formed with amine on the one end of the ligand molecule.
- might be a key principle for achieving dual inhibition bioactivity.