Study on the Anticancer Activity of Coumarin Derivatives by Molecular Modeling

• Published in: Chemical biology & drug design 2011-10, Vol.78 (4), p.651-658
• Main Authors: Huang, Xiao Y., Shan, Zhi J., Zhai, Hong L., Su, Li, Zhang, Xiao Y.
• Format: Article
• Language: English
• Subjects: anticancer activity; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor activity; Casein Kinase II - antagonists & inhibitors; Casein Kinase II - metabolism; CoMFA; CoMSIA; Coumarin; Coumarins - chemistry; Coumarins - pharmacology; docking; Drug Design; Drug development; Electrostatic properties; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Hydrogen; Hydrogen bonding; Hydrophobicity; Models, Molecular; Molecular modelling; Neoplasms - drug therapy; Oxygen; Protein Binding; Protein kinase; protein kinase 2; Quantitative Structure-Activity Relationship; Statistical analysis; Statistics
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/j.1747-0285.2011.01195.x

Protein kinase 2 (CK2) is a potential target, and the coumarins were identified as the attractive CK2 inhibitors. In this study, two models (CoMFA and CoMSIA) were established, and their reliabilities were supported by statistical parameters. From the CoMFA and CoMSIA models, the hydrophobic and hydrogen bonds play very important roles in the interactions between inhibitors and CK2, which were confirmed sufficiently by molecular docking. Furthermore, the binding mode of the inhibitors at the active sites of CK2 was also investigated by docking study. The hydroxyl at the position R5 is more important for coumarins inhibitors because it forms hydrogen bonds not only with Lys68 as hydrogen acceptor but also with H2O as hydrogen donor. In addition, hydroxyl can make electrostatic interactions with electropositive Lys68 residue. The large group at the R6 position is not conducive to inhibitor dock into the groove of the binding site of CK2. When there is nitro group, the electrostatic interaction between ligand and receptor is enhanced significantly, and the nitro oxygen can form hydrogen bonds with the backbone NH of Lys68 and Asp175 simultaneously. The results obtained from molecular modeling techniques not only provide the models to predict the activity of inhibitors but also lead to a better understanding of the interactions between inhibitors and CK2, which will be very helpful for drug design. Based on the reliable CoMFA CoMSIA models established, several key factors and active cites were obtained and explored, which were confirmed by molecular docking.