Abstract
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 r2pred > 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.
Highlights
Hsp90 belongs to a family of proteins called molecular chaperones that are responsible for maintaining the appropriate folding and three-dimensional conformation of proteins in the cell and are critical for controlling the balance between the synthesis and degradation of many proteins.they have been shown to play an important role in the stress response and in regulating many critical cellular functions, such as cell proliferation and apoptosis [1,2,3]
An effective 3D-QSAR model is generated by considering a number of statistical parameters, such as the cross-validated correlation coefficient (r2cv), non-cross-validated correlation coefficient (r2ncv), standard error estimate (SEE) and F-statistic values (F)
3D-QSAR studies on three kinds of Hsp90 inhibitors using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) based on ligand- and receptor-based methods have led to the identification of important structural features of steric, electrostatic, hydrophobic and H-bond donor interactions between the receptor and its ligand
Summary
Hsp belongs to a family of proteins called molecular chaperones that are responsible for maintaining the appropriate folding and three-dimensional conformation of proteins in the cell and are critical for controlling the balance between the synthesis and degradation of many proteins. They have been shown to play an important role in the stress response and in regulating many critical cellular functions, such as cell proliferation and apoptosis [1,2,3]. Hsp consists of a highly conserved N-terminal domain, a charged linker, and a highly conserved C-terminal region, the charged linker is not important for Hsp function, and the inhibitors of Hsp mainly bind to the N-and
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