Computer Aided Screening of Indirubin Analogues Targeting GSK-3β Protein Using Molecular Docking

Abstract

Objective: To study the inhibition effects of indirubin analogues with GSK-3β protein using molecular modeling and docking tools.

Materials and Methods: Crystal structure of GSK-3β was taken from Protein data bank (PDB ID: 1Q41). The construction and optimization of the three-dimensional structure of small molecules was done using ChemDraw and Chem3D version 18.1 (PerkinElmer®). All ligands and protein were prepared for docking using Auto Dock Tools (ADT) 1.5.6. AutoDock 4.2.6 was utilized for the molecular docking simulation.

Results: Overall, amongst 12 indirubin derivatives, 8 analogues appear to inhibit GSK-3β function based on docking score ranking, the formed hydrogen bonds of topmost compounds share same residues in the binding site as compared to standard indirubin- 3’-oxime.

Conclusion: Further in vitro and in vivo experimentation are needed to confirm the efficacy and potency of potential compounds. This model can be applied for design candidate drug with desired biological properties by chemical modification in functional group at appropriate places.

Keywords: Indirubin Derivatives; Docking; GSK-3β, Anti-Cancer

Abbreviations: PDB ID: Protein Data Bank; ADT: Auto Dock Tools; NSCLC: Non-Small-Cell Lung Cancer; SCLC: Small Cell Lung Cancer

Introduction

Lung cancer is one of the leading causes of cancer-related death worldwide both with men and women, it is responsible for about 1.3 million deaths annually [1,2]. In Vietnam, lung cancer has very high rate of mortality with 24,000 new cases annually in which 90% result in deaths. There are two major types of lung cancer: non-small-cell lung cancer (NSCLC) and small cell lung cancer (SCLC) [3,4]. Non-small cell lung cancer accounts for about 80% of overall lung cancer cases. Despite many efforts have been made in the last 25 years, the treatment drugs for patients remain poor efficacy. Indirubin and its analogues have been well known for their activities against many types of cancer cell line, mainly by inhibition of cell proliferation and induction of cell death [5,6]. These data suggest the development of indirubin derivatives as potential candidates for the treatment of lung cancer. Recent studies have discovered activity of GSK-3β in cancer and its role in regulating tumor cell profileration and survival of multiple human malignances. For the purpose of finding novel compounds and new idea for drug design, 12 analogues of indirubin were allowed to dock with GSK-3β protein.

Materials and Methods

Crystal structure of GSK-3β was taken from Protein data bank (PDB ID: 1Q41). The construction and optimization of the threedimensional structure of small molecules was done using Chem Draw and Chem3D version 18.1 (PerkinElmer®). All ligands and protein were prepared for docking using Auto Dock Tools (ADT) 1.5.6. The ligands and protein were protonated. The default Kollman charges and solvation parameters were allocated to the protein atoms. Gasteiger charges were added to each ligand atom. Grid box was generated around possible ligand-binding site. The precalculated binding affinity of each ligand’s atom type was prepared using Autogrid. Auto Dock 4.2.6 was utilized for the molecular docking simulation and Accelrys Discovery Studio Visualizer 4.0 was used for docking results visualization (Figure 1) and (Table 1).

Results

In general, 8 derivatives of indirubin showed better docking score to GSK-3β than the standard indirubin-3’-oxime. Most of the designed derivatives form H-bonds with GSK-3β when binding in its ATP-binding site. The hydrogen bonds occur mainly with VAL135 and ASP133 in the Hinge region and ARG14 which is the important region for the function of protein. In some of the molecules it also forms H-bonds with GLN185, LEU132, ASP200 and LYS88 amino acids of GSK-3β (Table 2).

Conflicts of interest

The authors declare that there is no conflict of interest.

Acknowledgement

Seung Hwa Hong, Kyu Sang Kyeong, Bang Yeon Hwang equally contributed to this work.

References

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Computer Aided Screening of Indirubin Analogues Targeting GSK-3β Protein Using Molecular Docking

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