Structure-Activity Relationship of Indole-Tethered Pyrimidine Derivatives that Concurrently Inhibit Epidermal Growth Factor Receptor and Other Angiokinases
Fig 5
Predicted docking orientation of MKP101 in the epidermal growth factor receptor (EGFR) kinase domain.
The binding poses of (A) MKP101 (carbon atoms in green) and (B) pazopanib (carbon atoms in orange) in the human EGFR kinase domain were compared. The structure of co-crystallized TAK-285 is shown as a reference (carbon atoms in off-white). Hydrogen bonds are displayed as dashed lines. The lipophilic potential surface of the ATP-binding site of EGFR was created using the MOLCAD implemented in Sybyl-X 2.0. A 2D-interaction diagram of the binding model of (C) MKP101 and (D) pazopanib was generated, which displayed amino acid residues within 4.0 Å of the ligand. Acidic, hydrophobic, basic, polar, and other residues at the active site are represented by red, green, purple, blue, and gray spheres, respectively. Hydrogen bonds between the ligand and the backbone are shown in dashed pink lines. The π-π stacking interaction is shown with a green line. The docking models show that MKP101 occupies the ATP-binding site in a manner similar to TAK-285, and the indole ring of MKP101 interacts with the backbone of the Phe856 by hydrogen bonding. However, as expected, pazopanib did not fit well at the ATP binding site. 2D, 2-dimensional; ATP, adenosine triphosphate.