Figure 6.

Binding modes of the 4 selected candidates in the substrate-binding site of GRP78 ATPase domain (PDB: 5F1X). (a, a′) ATP; (b, b′) EGCG; (c, c′) homoeriodictyol; (d, d′) isorhamnetin; and (e, e′) curcumin. The ATP docking was used to define the key residues in the catalytic site (Asp-34, Thr-38, Thr-39, Ile-61, Glu-201, Asp-224, Phe-258, Gly-228, Gly-249, Asp-249, Gly-364, Ser-365, Ile-368, and Asp-39). The active site is colored in orange. The 4 molecules have established at least 6 hydrogen bonds with these residues in GRP78. The best affinity was attributed to EGCG (–10.2 kcal/mol), higher than that of ATP (–9.6 kcal/mol). All molecules interact through hydrogen bonds with Gly-228, Phe-258, Asp-224 residues; EGCG established 3 other H bonds with Gly-364, Ser-365, and Ile-368. Homoeriodictyol, isorhamnetin, and curcumine interact through hydrophobic bonds with Thr-38 and Thr-39. EGCG indicates epigallocatechin gallate; GRP78, glucose-regulating protein 78.