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 (R2 = 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 ΔGbind,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).
Original language | English |
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Pages (from-to) | 4243-4247 |
Number of pages | 5 |
Journal | Bioorganic and Medicinal Chemistry Letters |
Volume | 21 |
Issue number | 14 |
DOIs | |
Publication status | Published - 15 Jul 2011 |
Scopus Subject Areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry
User-Defined Keywords
- Binding free energy
- Human glyoxalase I
- Indomethacin
- Inhibitory mechanism
- Kinetic analysis
- Molecular modeling