Prediction of new Hsp90 inhibitors based on 3,4-isoxazolediamide scaffold using QSAR study, molecular docking and molecular dynamic simulation

Maryam Abbasi,Massoud Amanlou,Hojjat Sadeghi-Aliabadi

doi:10.1186/s40199-017-0182-0

Abstract

BackgroundHeat shock protein90 (Hsp90) are overexpressed in tumor cells, so the inhibition of the Hsp90 ATPase activity would be a significantly effective strategy in cancer therapy.MethodsIn the current study, 3,4-isoxazolediamide derivatives were suggested as an Hsp90 inhibitor for anti-cancer therapy. Multiple linear regression (MLR) and genetic algorithm of partial least square (GA-PLS) methods were performed to build models to predict the inhibitory activity of Hsp90. The leave-one out (LOO) cross-validation and Y-randomization tests were performed to models’ validation. The new ligands were monitored by applicability domain. Molecular docking studies were also conducted to evaluate the mode of interaction of these compounds with Hsp90. Identification of the likely pathways into the active site pocket and the involved residues were performed by CAVAER 3.0.1 software. According to QSAR models and docking analysis, three new compounds were predicted. 50 ns molecular dynamic simulation was performed for the strongest synthesized compound and the best predicted compound in terms of binding energy and interactions between ligand and protein.ResultsThe made models showed the significance of size, shape, symmetry, and branching of molecules in inhibitory activities of Hsp90. Docking studies indicated that two hydroxyl groups in the resorcinol ring were important in interacting with Asp93 and the orientation of these groups was related to substitution of different R1 groups. Comparing of molecular dynamic simulation (MDs) results shows that new compound perched in active site with lower binding energy than the best synthesized compound.ConclusionThe QSAR and docking analyses shown to be beneficial tools in the proposal of anti-cancer activities and a leader to the synthesis of new Hsp90 inhibitors based 3,4-isoxazolediamide. The MDs confirmed that predicted ligand is steady in the Hsp90 active sites.Graphical

Highlights

Heat shock protein90 (Hsp90) are overexpressed in tumor cells, so the inhibition of the Hsp90 ATPase activity would be a significantly effective strategy in cancer therapy
The Hsp90 molecular chaperone contributes to folding of more than 200 proteins and it is necessary for adjusting the balance between the synthesis and degradation of many proteins in the cell [2, 3]
Client protein and co-chaperones bind to Hsp90 in the open condition of protein and Adenosine triphosphate (ATP) binds to N-terminal and Hsp90 will be closed

Summary

Introduction

Heat shock protein (Hsp90) are overexpressed in tumor cells, so the inhibition of the Hsp ATPase activity would be a significantly effective strategy in cancer therapy. Heat shock proteins (Hsps) play a critical role in maturation and stabilization of proteins in the cell [1]. One of the important Heat shock proteins in cell is Hsp. The Hsp molecular chaperone contributes to folding of more than 200 proteins (client proteins) and it is necessary for adjusting the balance between the synthesis and degradation of many proteins in the cell [2, 3]. The Hsp function is reliant on its ability to bind and hydrolyze ATP at the N-terminal domain. Client protein and co-chaperones bind to Hsp in the open condition of protein and ATP binds to N-terminal and Hsp will be closed. ATP is hydrolyzed, the complex is changed and client protein is folded (Fig. 1) [5]

Methods

Discussion

Conclusion