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Ligand and structure-based approaches for the exploration of structure–activity relationships of fusidic acid derivatives as antibacterial agents

Introduction: Fusidic acid (FA) has been widely applied in the clinical prevention and treatment of bacterial infections. Nonetheless, its clinical application has been limited due to its narrow antimicrobial spectrum and some side effects. Purpose: Therefore, it is necessary to explore the structur...

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Autores principales: Zheng, Wende, Tu, Borong, Zhang, Zhen, Li, Jinxuan, Yan, Zhenping, Su, Kaize, Deng, Duanyu, Sun, Ying, Wang, Xu, Zhang, Bingjie, Zhang, Kun, Wong, Wing-Leung, Wu, Panpan, Hong, Weiqian David, Ang, Song
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9852990/
https://www.ncbi.nlm.nih.gov/pubmed/36688047
http://dx.doi.org/10.3389/fchem.2022.1094841
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author Zheng, Wende
Tu, Borong
Zhang, Zhen
Li, Jinxuan
Yan, Zhenping
Su, Kaize
Deng, Duanyu
Sun, Ying
Wang, Xu
Zhang, Bingjie
Zhang, Kun
Wong, Wing-Leung
Wu, Panpan
Hong, Weiqian David
Ang, Song
author_facet Zheng, Wende
Tu, Borong
Zhang, Zhen
Li, Jinxuan
Yan, Zhenping
Su, Kaize
Deng, Duanyu
Sun, Ying
Wang, Xu
Zhang, Bingjie
Zhang, Kun
Wong, Wing-Leung
Wu, Panpan
Hong, Weiqian David
Ang, Song
author_sort Zheng, Wende
collection PubMed
description Introduction: Fusidic acid (FA) has been widely applied in the clinical prevention and treatment of bacterial infections. Nonetheless, its clinical application has been limited due to its narrow antimicrobial spectrum and some side effects. Purpose: Therefore, it is necessary to explore the structure–activity relationships of FA derivatives as antibacterial agents to develop novel ones possessing a broad antimicrobial spectrum. Methods and result: First, a pharmacophore model was established on the nineteen FA derivatives with remarkable antibacterial activities reported in previous studies. The common structural characteristics of the pharmacophore emerging from the FA derivatives were determined as those of six hydrophobic centers, two atom centers of the hydrogen bond acceptor, and a negative electron center around the C-21 field. Then, seven FA derivatives have been designed according to the reported structure–activity relationships and the pharmacophore characteristics. The designed FA derivatives were mapped on the pharmacophore model, and the Qfit values of all FA derivatives were over 50 and FA-8 possessed the highest value of 82.66. The molecular docking studies of the partial target compounds were conducted with the elongation factor G (EF-G) of S. aureus. Furthermore, the designed FA derivatives have been prepared and their antibacterial activities were evaluated by the inhibition zone test and the minimum inhibitory concentration (MIC) test. The derivative FA-7 with a chlorine group as the substituent group at C-25 of FA displayed the best antibacterial property with an MIC of 3.125 µM. Subsequently, 3D-QSAR was carried on all the derivatives by using the CoMSIA mode of SYBYL-X 2.0. Conclusion: Hence, a computer-aided drug design model was developed for FA, which can be further used to optimize FA derivatives as highly potent antibacterial agents.
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spelling pubmed-98529902023-01-21 Ligand and structure-based approaches for the exploration of structure–activity relationships of fusidic acid derivatives as antibacterial agents Zheng, Wende Tu, Borong Zhang, Zhen Li, Jinxuan Yan, Zhenping Su, Kaize Deng, Duanyu Sun, Ying Wang, Xu Zhang, Bingjie Zhang, Kun Wong, Wing-Leung Wu, Panpan Hong, Weiqian David Ang, Song Front Chem Chemistry Introduction: Fusidic acid (FA) has been widely applied in the clinical prevention and treatment of bacterial infections. Nonetheless, its clinical application has been limited due to its narrow antimicrobial spectrum and some side effects. Purpose: Therefore, it is necessary to explore the structure–activity relationships of FA derivatives as antibacterial agents to develop novel ones possessing a broad antimicrobial spectrum. Methods and result: First, a pharmacophore model was established on the nineteen FA derivatives with remarkable antibacterial activities reported in previous studies. The common structural characteristics of the pharmacophore emerging from the FA derivatives were determined as those of six hydrophobic centers, two atom centers of the hydrogen bond acceptor, and a negative electron center around the C-21 field. Then, seven FA derivatives have been designed according to the reported structure–activity relationships and the pharmacophore characteristics. The designed FA derivatives were mapped on the pharmacophore model, and the Qfit values of all FA derivatives were over 50 and FA-8 possessed the highest value of 82.66. The molecular docking studies of the partial target compounds were conducted with the elongation factor G (EF-G) of S. aureus. Furthermore, the designed FA derivatives have been prepared and their antibacterial activities were evaluated by the inhibition zone test and the minimum inhibitory concentration (MIC) test. The derivative FA-7 with a chlorine group as the substituent group at C-25 of FA displayed the best antibacterial property with an MIC of 3.125 µM. Subsequently, 3D-QSAR was carried on all the derivatives by using the CoMSIA mode of SYBYL-X 2.0. Conclusion: Hence, a computer-aided drug design model was developed for FA, which can be further used to optimize FA derivatives as highly potent antibacterial agents. Frontiers Media S.A. 2023-01-06 /pmc/articles/PMC9852990/ /pubmed/36688047 http://dx.doi.org/10.3389/fchem.2022.1094841 Text en Copyright © 2023 Zheng, Tu, Zhang, Li, Yan, Su, Deng, Sun, Wang, Zhang, Zhang, Wong, Wu, Hong and Ang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Chemistry
Zheng, Wende
Tu, Borong
Zhang, Zhen
Li, Jinxuan
Yan, Zhenping
Su, Kaize
Deng, Duanyu
Sun, Ying
Wang, Xu
Zhang, Bingjie
Zhang, Kun
Wong, Wing-Leung
Wu, Panpan
Hong, Weiqian David
Ang, Song
Ligand and structure-based approaches for the exploration of structure–activity relationships of fusidic acid derivatives as antibacterial agents
title Ligand and structure-based approaches for the exploration of structure–activity relationships of fusidic acid derivatives as antibacterial agents
title_full Ligand and structure-based approaches for the exploration of structure–activity relationships of fusidic acid derivatives as antibacterial agents
title_fullStr Ligand and structure-based approaches for the exploration of structure–activity relationships of fusidic acid derivatives as antibacterial agents
title_full_unstemmed Ligand and structure-based approaches for the exploration of structure–activity relationships of fusidic acid derivatives as antibacterial agents
title_short Ligand and structure-based approaches for the exploration of structure–activity relationships of fusidic acid derivatives as antibacterial agents
title_sort ligand and structure-based approaches for the exploration of structure–activity relationships of fusidic acid derivatives as antibacterial agents
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9852990/
https://www.ncbi.nlm.nih.gov/pubmed/36688047
http://dx.doi.org/10.3389/fchem.2022.1094841
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