Computational Tools Seminar

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Presentation transcript:

Computational Tools Seminar Hagar Tadmor Computational Tools Seminar

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

PI3K/mTOR & the Akt signaling pathway (1)

PI3K/mTOR & the Akt signaling pathway (2)

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.

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

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

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

Results (2) - SAR-table IC50 mTOR IC50 PI3k Core number R2 R1 Structure name 9.30 9.40 1 44473371 9.22 45379226 8.80 44546953

Results (3)-Observed and predicted activities mTOR PI3k CID predicted observed 9.30 9.30a 9.66 9.40a 44473371 8.93 9.22 9.41 45379226 8.68 8.80 9.27 44546953

Results (4)-PI3Kα-MAC Interactions

Results(5)-mTOR-MAC Interactions

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

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

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

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.