Induced-fit docking of mometasone furoate and further evidence for glucocorticoid receptor 17alpha pocket flexibility.

An induced-fit docking method was used to characterize the interactions of the glucocorticoid receptor binding-site with mometasone furoate, a glucocorticoid with a lipophilic ester at the C17alpha position. Two validation studies demonstrated that the protocol can reproduce crystal structures of nuclear receptors, and is appropriate for modeling ligand binding to the glucocorticoid receptor. Key hydrogen bonding interactions between mometasone furoate and the glucocorticoid receptor, as well as favorable hydrophobic interactions between the furoate group and the 17alpha pocket, contribute to high affinity and specificity of this ligand for the receptor. Using the glucocorticoid des-ciclesonide, which has an even larger moiety at the 16,17alpha position, induced-fit docking demonstrates the ability of the 17alpha pocket of the receptor to expand even further to accommodate the ligand.