Structural investigation into the inhibitory mechanisms of indomethacin and its analogues towards human glyoxalase I.

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Liu M, Yuan M, Li Z, Cheng YK, Luo HB, Hu X

Structural investigation into the inhibitory mechanisms of indomethacin and its analogues towards human glyoxalase I.

Bioorg Med Chem Lett. 2011 Jul 15;21(14):4243-7. doi: 10.1016/j.bmcl.2011.05.095. Epub 2011 Jun 1.

PubMed ID

21689932 [ View in PubMed

]

Abstract

In the present work, a combined study of kinetic analysis, molecular docking, and molecular dynamics simulations on indomethacin and its analogues is performed to better understand their inhibitory mechanisms towards human glyoxalase I (GLOI). A remarkable correlation (R(2)=0.974) was observed for six inhibitors including indomethacin between their experimental inhibitory affinities and predicted binding free energy parameter (DeltaG(bind,pred)). This suggests that DeltaG(bind,pred) of a GLOI/inhibitor complex can be efficiently used to interpolate the experimental inhibitory affinity of a ligand of similar nature in the GLOI enzyme system. Energetic analyses revealed that electrostatic contribution plays an important role in their inhibitory mechanisms, which reflects the significant contribution of the coordination bond between zinc and ligands. The present work highlights that indomethacin is a promising lead as GLOI inhibitors for further development since it may bind all subsites in the active site pocket of GLOI and stabilize the flexible loop (152-159).

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Indomethacin	Lactoylglutathione lyase	Ki (nM)	24400	N/A	N/A	Details