Structural Determination of Three Different Series of Compounds as Hsp90 Inhibitors Using 3D-QSAR Modeling, Molecular Docking and Molecular Dynamics Methods

International Journal of Molecular Sciences

Jianling Liu²  Fangfang Wang²  Zhi Ma¹  Xia Wang¹ 

[1] Center of Bioinformatics, Northwest A&F University, Yangling, Shaanxi 712100, China; E-Mails:;College of Life Sciences, Northwest University, Xi’an, Shaanxi 710069, China; E-Mails:

关键词: Hsp90;    3D-QSAR;    CoMFA;    CoMSIA;    molecular docking;    molecular dynamics;   

DOI  :  10.3390/ijms12020946

来源: mdpi

【 摘 要 】

Hsp90 is involved in correcting, folding, maturation and activation of a diverse array of client proteins; it has also been implicated in the treatment of cancer in recent years. In this work, comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), molecular docking and molecular dynamics were performed on three different series of Hsp90 inhibitors to build 3D-QSAR models, which were based on the ligand-based or receptor-based methods. The optimum 3D-QSAR models exhibited reasonable statistical characteristics with averaging internal q² > 0.60 and external r²_pred > 0.66 for Benzamide tetrahydro-4H-carbazol-4-one analogs (BT), AT13387 derivatives (AT) and Dihydroxylphenyl amides (DA). The results revealed that steric effects contributed the most to the BT model, whereas H-bonding was more important to AT, and electrostatic, hydrophobic, H-bond donor almost contributed equally to the DA model. The docking analysis showed that Asp93, Tyr139 and Thr184 in Hsp90 are important for the three series of inhibitors. Molecular dynamics simulation (MD) further indicated that the conformation derived from docking is basically consistent with the average structure extracted from MD simulation. These results not only lead to a better understanding of interactions between these inhibitors and Hsp90 receptor but also provide useful information for the design of new inhibitors with a specific activity.

【 授权许可】

CC BY   
© 2011 by the authors; licensee MDPI, Basel, Switzerland.