Structure-Activity Relationship of Indole-Tethered Pyrimidine Derivatives that Concurrently Inhibit Epidermal Growth Factor Receptor and Other Angiokinases
Fig 7
Comparison of the binding configurations of the MKP101 analogues.
(A) MKP102, (B) MKP103, (C) MKP104, and (D) MKP105 (carbon atoms in green) with TAK-285 (carbon atoms in ivory). 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. In the 2D-interaction diagram, 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 backbone are shown in dashed pink lines. The π-π stacking interaction is shown with a green line. Similar to MKP101, the 3-methyl indole moiety of MKP102 occupies a lipophilic pocket that forms a direct hydrogen bond with the backbone of Phe856. However, MKP103 the 2-methyl indole derivative, cannot fit into the lipophilic pocket because of the steric hindrance of the methyl group. The N-methyl indole MKP104 and the 6-amino indole MKP105 lost hydrogen bonding with Phe856 owing to the structural change. ATP, adenosine triphosphate; EGFR, epidermal growth factor receptor; 2D, 2-dimensional.