Skip to main content

Advertisement

Fig. 7 | Journal of Cheminformatics

Fig. 7

From: Data driven polypharmacological drug design for lung cancer: analyses for targeting ALK, MET, and EGFR

Fig. 7

Variability of aromatic side chain positions. a A view (from the N-lobe side of the ATP pocket) showing clustering of aromatic amino acids. In MET structures, Phe1223 (green) of the “DFG” motif clusters into the DFG-in or DFG-out positions, with an intermediate position also represented. Phe1089 (cyan) from the glycine-rich loop of MET usually clusters near the tip of an extended glycine-rich loop, but is also seen in several structures to occupy nearly exactly the position adopted by the DFG Phe1223 in protein DFG-out configurations. Tyr1230, when interacting with inhibitors, forms a tight cluster at a single position, but is absent when Phe1089 or Phe1223 occupies an adjacent site. The PDBID codes for these structures are 2RFN, 2RFS, 2WD1, 2WGJ, 2WKM, 3A4P, 3C1X, 3CCN, 3CD8, 3CE3, 3CTH, 3CTJ, 3DKF, 3DKG, 3EFK, 3F66, 3F82, 3I5N, 3L8V, 3LQ8, 3Q6W, 3QTI, 3R7O, 3RHK, 3U6H, 3U6I, 3ZXZ, 3ZZE, 4AOI, 4AP7, 4DEG, 4DEH, 4DEI, 4EEV, 4GG5, 4GG7, and 2YFX. b Inhibitor types cluster according to the clustering of the target structures. Generally, type II inhibitors (cyan), with some diversity of chemical scaffolds, often bind in part via packing against Phe1223 in its typical DFG-out position, while type I inhibitors (violet) often bind via pi–pi stacking interactions against Tyr1230. The exceptional geometry of both protein and inhibitor for Arq197 (yellow) is apparent. The PDBID codes for these structures are: 2RFN, 2RFS, 2WD1, 2WGJ, 2WKM, 3A4P, 3C1X, 3CCN, 3CD8, 3CE3, 3CTH, 3CTJ, 3DKF, 3EFJ, 3EFK, 3F66, 3F82, 3I5N, 3L8V, 3LQ8, 3QTI, 3RHK, 3VW8, 3ZXZ, 3ZZE, 4AOI, 4AP7, 4DEG, 4DEH, 4DEI, 4EEV, 4GG5, and 4GG7. c The pyrimidone inhibitor of MET structure 3EFJ binds via pi–pi stacking interactions, but the dimer resolved in the crystal shows that the protein can provide the partner for this interactions with two different side chains, with identical inhibitor binding geometries

Back to article page