Cargando…

Importance of the 2,6-Difluorobenzamide Motif for FtsZ Allosteric Inhibition: Insights from Conformational Analysis, Molecular Docking and Structural Modifications

A conformational analysis and molecular docking study comparing 2,6-difluoro-3-methoxybenzamide (DFMBA) with 3-methoxybenzamide (3-MBA) has been undertaken for investigating the known increase of FtsZ inhibition related anti S. aureus activity due to fluorination. For the isolated molecules, the cal...

Descripción completa

Detalles Bibliográficos
Autores principales: Barbier, Thibaut, Dumitrescu, Oana, Lina, Gérard, Queneau, Yves, Soulère, Laurent
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10003973/
https://www.ncbi.nlm.nih.gov/pubmed/36903302
http://dx.doi.org/10.3390/molecules28052055
_version_ 1784904728983896064
author Barbier, Thibaut
Dumitrescu, Oana
Lina, Gérard
Queneau, Yves
Soulère, Laurent
author_facet Barbier, Thibaut
Dumitrescu, Oana
Lina, Gérard
Queneau, Yves
Soulère, Laurent
author_sort Barbier, Thibaut
collection PubMed
description A conformational analysis and molecular docking study comparing 2,6-difluoro-3-methoxybenzamide (DFMBA) with 3-methoxybenzamide (3-MBA) has been undertaken for investigating the known increase of FtsZ inhibition related anti S. aureus activity due to fluorination. For the isolated molecules, the calculations reveal that the presence of the fluorine atoms in DFMBA is responsible for its non-planarity, with a dihedral angle of -27° between the carboxamide and the aromatic ring. When interacting with the protein, the fluorinated ligand can thus more easily adopt the non-planar conformation found in reported co-crystallized complexes with FtsZ, than the non-fluorinated one. Molecular docking studies of the favored non-planar conformation of 2,6-difluoro-3-methoxybenzamide highlights the strong hydrophobic interactions between the difluoroaromatic ring and several key residues of the allosteric pocket, precisely between the 2-fluoro substituent and residues Val203 and Val297 and between the 6-fluoro group and the residues Asn263. The docking simulation in the allosteric binding site also confirms the critical importance of the hydrogen bonds between the carboxamide group with the residues Val207, Leu209 and Asn263. Changing the carboxamide functional group of 3-alkyloxybenzamide and 3-alkyloxy-2,6-difluorobenzamide to a benzohydroxamic acid or benzohydrazide led to inactive compounds, confirming the importance of the carboxamide group.
format Online
Article
Text
id pubmed-10003973
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-100039732023-03-11 Importance of the 2,6-Difluorobenzamide Motif for FtsZ Allosteric Inhibition: Insights from Conformational Analysis, Molecular Docking and Structural Modifications Barbier, Thibaut Dumitrescu, Oana Lina, Gérard Queneau, Yves Soulère, Laurent Molecules Article A conformational analysis and molecular docking study comparing 2,6-difluoro-3-methoxybenzamide (DFMBA) with 3-methoxybenzamide (3-MBA) has been undertaken for investigating the known increase of FtsZ inhibition related anti S. aureus activity due to fluorination. For the isolated molecules, the calculations reveal that the presence of the fluorine atoms in DFMBA is responsible for its non-planarity, with a dihedral angle of -27° between the carboxamide and the aromatic ring. When interacting with the protein, the fluorinated ligand can thus more easily adopt the non-planar conformation found in reported co-crystallized complexes with FtsZ, than the non-fluorinated one. Molecular docking studies of the favored non-planar conformation of 2,6-difluoro-3-methoxybenzamide highlights the strong hydrophobic interactions between the difluoroaromatic ring and several key residues of the allosteric pocket, precisely between the 2-fluoro substituent and residues Val203 and Val297 and between the 6-fluoro group and the residues Asn263. The docking simulation in the allosteric binding site also confirms the critical importance of the hydrogen bonds between the carboxamide group with the residues Val207, Leu209 and Asn263. Changing the carboxamide functional group of 3-alkyloxybenzamide and 3-alkyloxy-2,6-difluorobenzamide to a benzohydroxamic acid or benzohydrazide led to inactive compounds, confirming the importance of the carboxamide group. MDPI 2023-02-22 /pmc/articles/PMC10003973/ /pubmed/36903302 http://dx.doi.org/10.3390/molecules28052055 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Barbier, Thibaut
Dumitrescu, Oana
Lina, Gérard
Queneau, Yves
Soulère, Laurent
Importance of the 2,6-Difluorobenzamide Motif for FtsZ Allosteric Inhibition: Insights from Conformational Analysis, Molecular Docking and Structural Modifications
title Importance of the 2,6-Difluorobenzamide Motif for FtsZ Allosteric Inhibition: Insights from Conformational Analysis, Molecular Docking and Structural Modifications
title_full Importance of the 2,6-Difluorobenzamide Motif for FtsZ Allosteric Inhibition: Insights from Conformational Analysis, Molecular Docking and Structural Modifications
title_fullStr Importance of the 2,6-Difluorobenzamide Motif for FtsZ Allosteric Inhibition: Insights from Conformational Analysis, Molecular Docking and Structural Modifications
title_full_unstemmed Importance of the 2,6-Difluorobenzamide Motif for FtsZ Allosteric Inhibition: Insights from Conformational Analysis, Molecular Docking and Structural Modifications
title_short Importance of the 2,6-Difluorobenzamide Motif for FtsZ Allosteric Inhibition: Insights from Conformational Analysis, Molecular Docking and Structural Modifications
title_sort importance of the 2,6-difluorobenzamide motif for ftsz allosteric inhibition: insights from conformational analysis, molecular docking and structural modifications
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10003973/
https://www.ncbi.nlm.nih.gov/pubmed/36903302
http://dx.doi.org/10.3390/molecules28052055
work_keys_str_mv AT barbierthibaut importanceofthe26difluorobenzamidemotifforftszallostericinhibitioninsightsfromconformationalanalysismoleculardockingandstructuralmodifications
AT dumitrescuoana importanceofthe26difluorobenzamidemotifforftszallostericinhibitioninsightsfromconformationalanalysismoleculardockingandstructuralmodifications
AT linagerard importanceofthe26difluorobenzamidemotifforftszallostericinhibitioninsightsfromconformationalanalysismoleculardockingandstructuralmodifications
AT queneauyves importanceofthe26difluorobenzamidemotifforftszallostericinhibitioninsightsfromconformationalanalysismoleculardockingandstructuralmodifications
AT soulerelaurent importanceofthe26difluorobenzamidemotifforftszallostericinhibitioninsightsfromconformationalanalysismoleculardockingandstructuralmodifications