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.
School of Pharmaceutical Science, Sun Yat-sen University, Guangzhou 510006, China.
Minggui
M
Yuan
Minxian
M
Luo
Yao
Y
Song
Qiu
Q
Xu
Xiaofeng
X
Wang
Yi
Y
Cao
Xianzhang
X
Bu
Yanliang
Y
Ren
Xiaopeng
X
Hu
D003474:Curcumin / Q000031:analogs & derivatives* / Q000032:analysis / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D005822:Genetic Vectors; D006801:Humans; D020128:Inhibitory Concentration 50; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D010957:Plasmids; D011485:Protein Binding; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007791:Lactoylglutathione Lyase; D003474:Curcumin