Efficacy of some natural flavanoids against PDK-1 Kinase: An insilico Molecular docking and Molecular Dynamic Simulation study

Author Name(s): Shalini Singh, *Pradeep Srivastava
Author Email: drpradeep19@gmail.com

Abstract

PDK-1, 63Da serine thionine kinase has a well-known role in cell growth regulation and differentiation. It is over expressed in many cancer cells and considered as a novel target of many anti-cancer drugs. In the present study we have explored the affinity and interaction of some plant derived natural flavanoids against PDK-1 with insilico molecular docking and molecular dynamic simulation approach. Ten plant derived natural flavanoids were docked in to the ATP binding site of PDK-1, using the CDOCCER molecular docking program implemented in Discovery studio 2.5 to identify the potential hits against PDK-1.Myricetin, Epigallocatechin, Querecetin and Hesperitin showed high docking score as well as the interaction with hinge region and active stites amino actids .Finally highest docking hit (myrecetin) was subjected to molecular dynamic simulation study, evaluating the binding staibility of complex under body environmental conditions. GROMACS 4.5 program.RMSD profile of PDK-1 alone as well as PDK-1 and myricetin complex during 10 ns simulation were always less than 5.0 Å (0.5 nm) during entire simulation, suggesting the stability of simulation system during whole simutaltion. Molecular docking and molecular dynamic simulation resulats revealed that natural flavanoids (especially myricetin) act as PDK-1 inhibitors to combat cancer.

Keywords

PDK-1, anticancer drug, CDOCKER, GROMACS 4.5, 10ns

Introduction

Protein kinases are significant components of cell signaling pathway [1]. Protein kinases are considered as second largest group of drug target [2]. Phosphoinositide-dependent kinase-1 (PDK-1), a 63 kDa serine/threonine kinase, is a major player in the PI3-kinase signaling pathway that regulates gene expression, cell cycle, growth, and proliferation [3–10]. Many researches discover that 3-phosphoinositide- dependent protein kinase-1 (PDK-1) is overexpressed in many cancer cells [11]. PDK-1 has been termed the ‘‘Master kinase’’ because it phosphorylates highly conserved serine or threonine residues in the T-loop (or activation loop) of numerous AGC kinases, including PKB/AKT, PKC, p70S6K, SGK, and PDK-1 itself [12]. Although the precise regulatory mechanisms vary, in the case of PKB/AKT, activation by PDK-1 is critically dependent upon prior PI3 kinase activation and the presence of phosphatidylinositol-(3,4,5)- triphosphate (PIP3).
A significant proportion (40–50%) of all tumors involve mutations in PIP3-3-phosphatase (PTEN) [13–16], which results in elevated levels of PIP3 and enhanced activation of PKB/ AKT, p70S6K, and SGK. Inhibitors of PDK-1 could potentiallyprovide valuable therapeutic agents for the treatment of cancer. Although a enormous number of natural compounds have been reported to possess anticancer properties, their mechanisms of action are not well understood. Natural Flavonoids are class of compounds, widely spread in the vegetables and fruits, presently consumed in huge amount in the daily diet. In recent years, flavonoids and their synthetic analogues have been intensely investigated in the treatment of ovarian, breast, cervical, pancreatic, and prostate cancer. To some extent, chemical structures of flavonoids will influence their anticancer activities.
Thus, the present study was on the inhibitory action of some selected natural flavanoids against PDK-1. These selected compouns were inetially subjected to the molecular docking study by using CDOCCKER program. Finally the best hit (Myrecetin) was further subjected to the molecular dynamic simulation study to evaluate the binding stability of the PDK-1-Myrecetin complex during entire simulation using GROMACS 4.5.

Conclusion

This study involved a comparative evaluation of various natural flavanoids as potential anticancer compounds wherein the effectiveness has been studied with reference to PDK- 1 Kinase inhibition. The molecular docking results showed the effectiveness of three natural flavanoids among all the compounds taken for the study. Finally best hit ie myrecetin was subjected to molecular dynamic simulation study, evaluating the binding staibility of complex under body environmental conditions. The simulation results have been evaluated with reference to Protein Ligand interaction and molecular dynamic simulation in water. These studies depict that the role of some crucial amino acids involved in proper binding of inhibitors with the active site of PDK-1 can be useful for designing better drugs to combat cancer. Further, these studies support the potential role of myrecetin in cancer which should be further studied for modulation of other signaling pathways as PDK-1 kinase being master regulators of other down straem regulators protein PIP3 kinase, AKT kinase.

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