Binding mechanism of caffeic acid and simvastatin to the integrin linked kinase for therapeutic implications: a comparative docking and MD simulation studies

Abstract

Integrin linked kinase (ILK) is a Ser/Thr kinase, which regulates various integrin mediated signaling pathways, and is involved in cell adhesion, migration and differentiation. Alteration in the ILK is responsible for abnormal functioning of the cell system, which may lead to the cancer progression and metastasis. Caffeic acid (CA) and simvastatin are used as antioxidant and possess anticancer properties. Thus, inhibiting the kinase activity of ILK by CA and simvastatin may be implicated in the cancer therapy. In this study, we have performed molecular docking followed by 100 ns MD simulations to understand the interaction mechanism of ILK protein with the CA and simvastatin. Average potential energy was found to be highest in case of ILK–CA complex (−770,949 kJ/mol). Binding free energy was found to be higher in case of simvastatin than CA. Our results indicate that simvastatin binds more effectively to the active pocket of ILK. We further performed MTT assay to understand its anticancer potential. Simvastatin shows the IC₅₀ values for HepG2 and MCF-7 as 19.18 ± 0.12 and 13.84 ± 0.22 µM, respectively. However, the IC₅₀ value of CA on HepG2 and MCF-7 was reported as 175.50 ± 1.44 and 144.90 ± 1.53 µM, respectively. Our study provides a deeper insight into the binding mechanism of simvastatin and CA to ILK, which further opens a promising channel for their implications in cancer therapy.

Keywords:

• Integrin-linked kinase
• caffeic acid
• simvastatin: MD simulation
• kinase inhibitor

Acknowledgements

M.G. is grateful to the Sharda University for Ph.D. fellowship. F.I.K. thanks the Centre for High Performance Computing (CHPC), South Africa. We thank Department of Science and Technology, India, for FIST support.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

M.I.H. thanks the Department of Science and Technology (India) for financial support.