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Probing In Silico the Benzimidazole Privileged Scaffold for the Development of Drug-like Anti-RSV Agents

Targeting the fusion (F) protein has been recognized as a fruitful strategy for the development of anti-RSV agents. Despite the considerable efforts so far put into the development of RSV F protein inhibitors, the discovery of adequate therapeutics for the treatment of RSV infections is still awaiti...

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Autores principales: Cichero, Elena, Calautti, Alessio, Francesconi, Valeria, Tonelli, Michele, Schenone, Silvia, Fossa, Paola
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8707824/
https://www.ncbi.nlm.nih.gov/pubmed/34959708
http://dx.doi.org/10.3390/ph14121307
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author Cichero, Elena
Calautti, Alessio
Francesconi, Valeria
Tonelli, Michele
Schenone, Silvia
Fossa, Paola
author_facet Cichero, Elena
Calautti, Alessio
Francesconi, Valeria
Tonelli, Michele
Schenone, Silvia
Fossa, Paola
author_sort Cichero, Elena
collection PubMed
description Targeting the fusion (F) protein has been recognized as a fruitful strategy for the development of anti-RSV agents. Despite the considerable efforts so far put into the development of RSV F protein inhibitors, the discovery of adequate therapeutics for the treatment of RSV infections is still awaiting a positive breakthrough. Several benzimidazole-containing derivatives have been discovered and evaluated in clinical trials, with only some of them being endowed with a promising pharmacokinetic profile. In this context, we applied a computational study based on a careful analysis of a number of X-ray crystallographic data of the RSV F protein, in the presence of different clinical candidates. A deepen comparison of the related electrostatic features and H-bonding motifs allowed us to pave the way for the following molecular dynamic simulation of JNJ-53718678 and then to perform docking studies of the in-house library of potent benzimidazole-containing anti-RSV agents. The results revealed not only the deep flexibility of the biological target but also the most relevant and recurring key contacts supporting the benzimidazole F protein inhibitor ability. Among them, several hydrophobic interactions and π-π stacking involving F140 and F488 proved to be mandatory, as well as H-bonding to D486. Specific requirements turning in RSV F protein binding ability were also explored thanks to structure-based pharmacophore analysis. Along with this, in silico prediction of absorption, distribution, metabolism, excretion (ADME) properties, and also of possible off-target events was performed. The results highlighted once more that the benzimidazole ring represents a privileged scaffold whose properties deserve to be further investigated for the rational design of novel and orally bioavailable anti-RSV agents.
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spelling pubmed-87078242021-12-25 Probing In Silico the Benzimidazole Privileged Scaffold for the Development of Drug-like Anti-RSV Agents Cichero, Elena Calautti, Alessio Francesconi, Valeria Tonelli, Michele Schenone, Silvia Fossa, Paola Pharmaceuticals (Basel) Article Targeting the fusion (F) protein has been recognized as a fruitful strategy for the development of anti-RSV agents. Despite the considerable efforts so far put into the development of RSV F protein inhibitors, the discovery of adequate therapeutics for the treatment of RSV infections is still awaiting a positive breakthrough. Several benzimidazole-containing derivatives have been discovered and evaluated in clinical trials, with only some of them being endowed with a promising pharmacokinetic profile. In this context, we applied a computational study based on a careful analysis of a number of X-ray crystallographic data of the RSV F protein, in the presence of different clinical candidates. A deepen comparison of the related electrostatic features and H-bonding motifs allowed us to pave the way for the following molecular dynamic simulation of JNJ-53718678 and then to perform docking studies of the in-house library of potent benzimidazole-containing anti-RSV agents. The results revealed not only the deep flexibility of the biological target but also the most relevant and recurring key contacts supporting the benzimidazole F protein inhibitor ability. Among them, several hydrophobic interactions and π-π stacking involving F140 and F488 proved to be mandatory, as well as H-bonding to D486. Specific requirements turning in RSV F protein binding ability were also explored thanks to structure-based pharmacophore analysis. Along with this, in silico prediction of absorption, distribution, metabolism, excretion (ADME) properties, and also of possible off-target events was performed. The results highlighted once more that the benzimidazole ring represents a privileged scaffold whose properties deserve to be further investigated for the rational design of novel and orally bioavailable anti-RSV agents. MDPI 2021-12-15 /pmc/articles/PMC8707824/ /pubmed/34959708 http://dx.doi.org/10.3390/ph14121307 Text en © 2021 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
Cichero, Elena
Calautti, Alessio
Francesconi, Valeria
Tonelli, Michele
Schenone, Silvia
Fossa, Paola
Probing In Silico the Benzimidazole Privileged Scaffold for the Development of Drug-like Anti-RSV Agents
title Probing In Silico the Benzimidazole Privileged Scaffold for the Development of Drug-like Anti-RSV Agents
title_full Probing In Silico the Benzimidazole Privileged Scaffold for the Development of Drug-like Anti-RSV Agents
title_fullStr Probing In Silico the Benzimidazole Privileged Scaffold for the Development of Drug-like Anti-RSV Agents
title_full_unstemmed Probing In Silico the Benzimidazole Privileged Scaffold for the Development of Drug-like Anti-RSV Agents
title_short Probing In Silico the Benzimidazole Privileged Scaffold for the Development of Drug-like Anti-RSV Agents
title_sort probing in silico the benzimidazole privileged scaffold for the development of drug-like anti-rsv agents
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8707824/
https://www.ncbi.nlm.nih.gov/pubmed/34959708
http://dx.doi.org/10.3390/ph14121307
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