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 (K(i)) values of compounds 8, 9, 10, 11 and 13 to GLO I are 4.600µM, 2.600µM, 3.200µM, 3.600µM and 3.600µM, 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 q(2) value is 0.638 while no-validation r(2) 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.

Binding of curcumin with glyoxalase I: Molecular docking, molecular dynamics simulations, and kinetics analysis.

Glyoxalase I (GLOI) is a key metalloenzyme in glycolytic pathway by detoxifying reactive alpha-ketoaldehydes such as methylglyoxal. Recent studies demonstrate that the nature product curcumin is an efficient inhibitor of GLOI, but its binding mechanism towards GLOI is still unclear. In the present study, molecular docking and molecular dynamics (MD) simulations were performed to better understand the inhibitory mechanism of curcumin towards GLOI. The enol form of curcumin coordinates with the catalytic zinc ion of GLOI and forms a strong hydrogen bond with Glu 172, whereas its keto tautomer displays unfavorable electrostatic interactions with Glu 172 and Glu 99. The calculated binding free energies suggest that GLOI prefers the primary enol form (DeltaG=-30.38kcal/mol) to the keto tautomer (DeltaG=-24.16kcal/mol). The present work also reveals that bisdemethoxycurcumin binds to GLOI in a similar manner as curcumin and exhibits a slightly less negative predicted binding free energy, which is further validated by our comparative kinetics analysis (Ki=18.2 and 10.3muM for bisdemethoxycurcumin and curcumin, respectively). Results of the study can provide an insight into the development of novel and more effective GLOI inhibitors.