A comparative reverse docking strategy to identify potential antineoplastic targets of tea functional components and binding mode.

Tuan-Sheng Chen,Rong Zheng,Tun Lu

doi:10.3390/ijms12085200

Abstract

The main functional components of green tea, such as epigallocatechin gallate (EGCG), epigallocatechin (EGC), epicatechin gallate (ECG) and epicatechin (EC), are found to have a broad antineoplastic activity. The discovery of their targets plays an important role in revealing the antineoplastic mechanism. Therefore, to identify potential target proteins for tea polyphenols, we have taken a comparative virtual screening approach using two reverse docking systems, one based on Autodock software and the other on Tarfisdock. Two separate in silico workflows were implemented to derive a set of target proteins related to human diseases and ranked by the binding energy score. Several conventional clinically important proteins with anti-tumor effects are screened out from the PDTD protein database as the potential receptors by both procedures. To further analyze the validity of docking results, we study the binding mode of EGCG and the potential target protein Leukotriene A4 hydrolase in detail. We indicate that interactions mediated by electrostatic and hydrogen bond play a key role in ligand binding. EGCG binds to the enzyme with certain orientation and conformation that is suitable for nucleophilic attacks by several electrical residues inside the enzyme’s activity cavity. This study provides useful information for studying the antitumor mechanism of tea’s functional components. The comparative reverse docking strategy presented generates a tractable set of antineoplastic proteins for future experimental validation as drug targets against tumors.

Highlights

Green tea is a popular beverage worldwide, and it has been found to have a relatively strong antineoplastic effect
Tea functional components studied in this work include epigallocatechin gallate (EGCG), epicatechin gallate (ECG), epigallocatechin (EGC) and epicatechin (EC)
In Equation (2), the total energy is composed of van der Waals energy and electrostatic energy. In both Equation (1) and (2), each term is a double sum over ligand atoms i and receptor atoms j; rij is the distance between atom i and atom j; Aij, Bij, Cij and Dij are van der Waals repulsion and attraction parameters, respectively; a and b are the van der Waals repulsion and attraction exponents, respectively; qi and qj are point charges on atoms i and j; D and ε(r) are dielectric constant; and 332.0 is the factor that converts the electrostatic energy into kcal/mol. Comparing these two docking procedures’ results, we find that EGCG and ECG share a common best receptor: Leukotriene A4 hydrolase, for its lower binding energy get by both procedures

Summary

Introduction

Green tea is a popular beverage worldwide, and it has been found to have a relatively strong antineoplastic effect. In contrast to EGCG, studies on ECG, EGC and EC have rarely been reported, especially regarding their biological activity mechanism. Et al developed a reverse docking web server, Tarfisdock [10], and used it to identify drug targets These pioneering researches indicate that reverse docking procedures can be used to identify the target proteins of tea polyphenols. We take a comparative virtual screening approach which uses both the reverse docking system based on Autodock and the Tarfisdock system, to identify potential target proteins for tea polyphenols. Our work helps to design new targeted drugs with strong antineoplastic effects by providing the information about the binding mechanism of tea polyphenols to key putative receptor proteins

Potential Protein Targets for EGCG

Comparing Screening Results of Autodock and Tarfisdock

Binding Mode between Leukotriene A4 Hydrolase and EGCG

The Three-Dimensional Structures of Tea Polyphenols and Drug Targets

Reverse Docking Procedure Using Autodock and Tarfisdock

Conclusions