title: Structural investigation into the inhibitory mechanisms of indomethacin and its analogues towards human glyoxalase I.
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 (ΔG(bind,pred)). This suggests that ΔG(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).
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China.
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.forename: Minggui
authors.initials: M
authors.lastname: Yuan
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
authors.forename: Yuen-Kit
authors.initials: YK
authors.lastname: Cheng
authors.forename: Hai-Bin
authors.initials: HB
authors.lastname: Luo
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Hu
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D006801:Humans; D007213:Indomethacin / Q000031:analogs & derivatives* / Q000494:pharmacology; D007700:Kinetics; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D013816:Thermodynamics
chemical_list: D007791:Lactoylglutathione Lyase; D007213:Indomethacin