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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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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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. |
format | Online Article Text |
id | pubmed-8707824 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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