Identification of curcumin derivatives as human glyoxalase I inhibitors: A combination of biological evaluation, molecular docking, 3D-QSAR and molecular dynamics simulation studies

Several recent developments suggest that the human glyoxalase I (GLO I) is a potential target for anti-tumor drug development. In present study, a series of curcumin derivatives with high inhibitory activity against human GLO I were discovered. Inhibition constant (Ki) values of compounds 8, 9, 10, 11 and 13 to GLO I are 4.600 μM, 2.600 μM, 3.200 μM, 3.600 μM and 3.600 μM, respectively. To elucidate the structural features of potent inhibitors, docking-based three-dimensional structure–activity relationship (3D-QSAR) analyses were performed. Satisfactory agreement between experiment and theory suggests that comparative molecular similarity index analysis (CoMSIA) modeling exhibit much better correlation and predictive power. The cross-validated q2 value is 0.638 while no-validation r2 value is 0.930. Integrated with docking-based 3D-QSAR CoMSIA modeling, molecular surface property (electrostatic and steric) mapping and molecular dynamics simulation, a set of receptor-ligand binding models and bio-affinity predictive models for rational design of more potent inhibitors of GLO I are established.

We designed, synthesized and tested a series of curcumin derivatives possessing high inhibitory activity against human GLO I, the binding model for compound 8 was obtained by MD simulations, as shown in Figure 7. The satisfactory correlation of pKi value between experiment and theory was shown in Figure 8.Figure optionsDownload as PowerPoint slide