3D-QSAR and docking studies of flavonoids as potent Escherichia coli inhibitors.

Yajing Fang,Xiaojuan Qi,Xiaoyun Xu,Ting Wu,Xixi Zang,Siyi Pan,Yulin Lu

doi:10.1038/srep23634

Abstract

Flavonoids are potential antibacterial agents. However, key substituents and mechanism for their antibacterial activity have not been fully investigated. The quantitative structure-activity relationship (QSAR) and molecular docking of flavonoids relating to potent anti-Escherichia coli agents were investigated. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were developed by using the pIC50 values of flavonoids. The cross-validated coefficient (q2) values for CoMFA (0.743) and for CoMSIA (0.708) were achieved, illustrating high predictive capabilities. Selected descriptors for the CoMFA model were ClogP (logarithm of the octanol/water partition coefficient), steric and electrostatic fields, while, ClogP, electrostatic and hydrogen bond donor fields were used for the CoMSIA model. Molecular docking results confirmed that half of the tested flavonoids inhibited DNA gyrase B (GyrB) by interacting with adenosine-triphosphate (ATP) pocket in a same orientation. Polymethoxyl flavones, flavonoid glycosides, isoflavonoids changed their orientation, resulting in a decrease of inhibitory activity. Moreover, docking results showed that 3-hydroxyl, 5-hydroxyl, 7-hydroxyl and 4-carbonyl groups were found to be crucial active substituents of flavonoids by interacting with key residues of GyrB, which were in agreement with the QSAR study results. These results provide valuable information for structure requirements of flavonoids as antibacterial agents.

Highlights

The abuse of synthetic antibiotics has contributed to the increased incidence of bacterial resistance to available antibacterial agents, resulting in an urgent need for natural antimicrobials[1]
It is important to note that additional information relating the structure requirements for flavonoids as antibacterial agents have been depicted in 3D-quantitative structure-activity relationship (QSAR) models than the limited results in the Structure activity relationships (SAR) studies
The results obtained in both Comparative molecular field analysis (CoMFA)-CSE and comparative molecular similarity indices analysis (CoMSIA)-CDE models were in agreement with previous studies, including the favorable negative charges at C-330, C-727, C-8 and C-2′ 31 and favorable positive charges at C-4′ 22

Summary

Introduction

The abuse of synthetic antibiotics has contributed to the increased incidence of bacterial resistance to available antibacterial agents, resulting in an urgent need for natural antimicrobials[1]. The antibacterial activities of flavonoids have been reported to be related to their chemical structures[6]. 3D-QSAR studies, mainly focus on how changes in 3D structural features such as electrostatic distribution, hydrophobic distribution[6], hydrogen bond (H-bond) forming ability and orientation[11] of chemical groups affect biological activity. In docking studies, quercetin and epigallocatechin gallate (EGCG) have been reported to be potent GyrB inhibitors by competitively replacing ATP in the ATP binding pocket of GyrB20,23, resulting in the inhibition of DNA supercoiling activity. To observe the effect of structure of flavonoids on their antibacterial activity, two 3D-QSAR models were developed by using two methods, CoMFA and CoMSIA. The main objectives of this study are to relate structure requirements of flavonoids to antibacterial activity and provide an explanation of the mechanism of flavonoids inhibiting GyrB.

Objectives

Methods

Results

Conclusion