Rationalization of physicochemical characters and docking of 3-alkoxy-5-phenoxy-N-thiazolyl benzamide analogs toward glucokinase activator activity

摘要

Diabetes mellitus is a chronic metabolic disorder involving the dysregulation of glucose metabolism, β-cell dysfunction, and impaired insulin sensitivity. Glucokinase (GK) promotes glycogen synthesis, while it enhances insulin secretion from pancreatic β-cells. In this study, we focused on molecular modeling study of 3-alkoxy-5-phenoxy-N-thiazolyl benzamide analogs with reference to structural requirements. The amalgamated best fit consensus scoring function showed coefficient of determination (0.927), leave-one-out cross-validated squared correlation coefficient (0.865), and external predictivity value (0.763). The binding of 3-alkoxy-5-phenoxy-N-thiazolyl benzamide analogs to glucokinase enzyme was explored with the help of docking. The most stable ligand–enzyme complex of compound TR-2 showed that the NH of the benzamide make key hydrogen bonds with the backbone C=O of Arg63. The phenoxy moiety on the 5th position of benzene ring occupies the hydrophobic space on the allosteric binding site constituted from Met210, Met235, Cys220, and Tyr214. One of the oxygen of methylsulfonyl group forms hydrogen bond with NE2 of Gln98 and phenyl ring and the aromatic ring of Tyr215 are perpendicular to each other, which probably increase potency due to van der Waals interactions.The structural insights gleaned from the study could be usefully employed to design activators with a much more enhanced potency.