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Hagar Tadmor Computational Tools Seminar PI3K/Akt signaling pathway Research aim & rationale Methods Results Conclusions & Future thoughts 2 PI3K/mTOR & the Akt signaling pathway (1) 3 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. 5 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 6 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 7 Results (1) - Pharmacophore model MAC of PI3Ka. Pink: HB acceptor light blue: HB donor purple: positive feature orange ring: aromatic ring 8 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 9 Results (3)-Observed and predicted activities 10 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 11 Results(5)-mTOR-MAC Interactions 12 Results (6)-Ligand interaction diagram -PI3Kα in docked complex structure for the MAC(A) and LAC(B) 13 Results (7)-Ligand interaction diagram mTOR in docked complex structure for the MAC(A) and the LAC(B) 14 Results (8)-Ligand interaction diagram showing residues near PKI-587 in docked complex structure PI3k (A), Mtor (B) 15 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 16 LAC differed by one HB formed with the one end of the ligand molecule. be a key principle for achieving dual bioactivity. 17 18