Cargando…
Targeting Beta-Blocker Drug–Drug Interactions with Fibrinogen Blood Plasma Protein: A Computational and Experimental Study
In this work, one of the most prevalent polypharmacology drug–drug interaction events that occurs between two widely used beta-blocker drugs—i.e., acebutolol and propranolol—with the most abundant blood plasma fibrinogen protein was evaluated. Towards that end, molecular docking and Density Function...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699576/ https://www.ncbi.nlm.nih.gov/pubmed/33228181 http://dx.doi.org/10.3390/molecules25225425 |
_version_ | 1783616080329048064 |
---|---|
author | González-Durruthy, Michael Concu, Riccardo Vendrame, Laura F. Osmari Zanella, Ivana Ruso, Juan M. Cordeiro, M. Natália D. S. |
author_facet | González-Durruthy, Michael Concu, Riccardo Vendrame, Laura F. Osmari Zanella, Ivana Ruso, Juan M. Cordeiro, M. Natália D. S. |
author_sort | González-Durruthy, Michael |
collection | PubMed |
description | In this work, one of the most prevalent polypharmacology drug–drug interaction events that occurs between two widely used beta-blocker drugs—i.e., acebutolol and propranolol—with the most abundant blood plasma fibrinogen protein was evaluated. Towards that end, molecular docking and Density Functional Theory (DFT) calculations were used as complementary tools. A fibrinogen crystallographic validation for the three best ranked binding-sites shows 100% of conformationally favored residues with total absence of restricted flexibility. From those three sites, results on both the binding-site druggability and ligand transport analysis-based free energy trajectories pointed out the most preferred biophysical environment site for drug–drug interactions. Furthermore, the total affinity for the stabilization of the drug–drug complexes was mostly influenced by steric energy contributions, based mainly on multiple hydrophobic contacts with critical residues (THR22: P and SER50: Q) in such best-ranked site. Additionally, the DFT calculations revealed that the beta-blocker drug–drug complexes have a spontaneous thermodynamic stabilization following the same affinity order obtained in the docking simulations, without covalent-bond formation between both interacting beta-blockers in the best-ranked site. Lastly, experimental ultrasound density and velocity measurements were performed and allowed us to validate and corroborate the computational obtained results. |
format | Online Article Text |
id | pubmed-7699576 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-76995762020-11-29 Targeting Beta-Blocker Drug–Drug Interactions with Fibrinogen Blood Plasma Protein: A Computational and Experimental Study González-Durruthy, Michael Concu, Riccardo Vendrame, Laura F. Osmari Zanella, Ivana Ruso, Juan M. Cordeiro, M. Natália D. S. Molecules Article In this work, one of the most prevalent polypharmacology drug–drug interaction events that occurs between two widely used beta-blocker drugs—i.e., acebutolol and propranolol—with the most abundant blood plasma fibrinogen protein was evaluated. Towards that end, molecular docking and Density Functional Theory (DFT) calculations were used as complementary tools. A fibrinogen crystallographic validation for the three best ranked binding-sites shows 100% of conformationally favored residues with total absence of restricted flexibility. From those three sites, results on both the binding-site druggability and ligand transport analysis-based free energy trajectories pointed out the most preferred biophysical environment site for drug–drug interactions. Furthermore, the total affinity for the stabilization of the drug–drug complexes was mostly influenced by steric energy contributions, based mainly on multiple hydrophobic contacts with critical residues (THR22: P and SER50: Q) in such best-ranked site. Additionally, the DFT calculations revealed that the beta-blocker drug–drug complexes have a spontaneous thermodynamic stabilization following the same affinity order obtained in the docking simulations, without covalent-bond formation between both interacting beta-blockers in the best-ranked site. Lastly, experimental ultrasound density and velocity measurements were performed and allowed us to validate and corroborate the computational obtained results. MDPI 2020-11-19 /pmc/articles/PMC7699576/ /pubmed/33228181 http://dx.doi.org/10.3390/molecules25225425 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article González-Durruthy, Michael Concu, Riccardo Vendrame, Laura F. Osmari Zanella, Ivana Ruso, Juan M. Cordeiro, M. Natália D. S. Targeting Beta-Blocker Drug–Drug Interactions with Fibrinogen Blood Plasma Protein: A Computational and Experimental Study |
title | Targeting Beta-Blocker Drug–Drug Interactions with Fibrinogen Blood Plasma Protein: A Computational and Experimental Study |
title_full | Targeting Beta-Blocker Drug–Drug Interactions with Fibrinogen Blood Plasma Protein: A Computational and Experimental Study |
title_fullStr | Targeting Beta-Blocker Drug–Drug Interactions with Fibrinogen Blood Plasma Protein: A Computational and Experimental Study |
title_full_unstemmed | Targeting Beta-Blocker Drug–Drug Interactions with Fibrinogen Blood Plasma Protein: A Computational and Experimental Study |
title_short | Targeting Beta-Blocker Drug–Drug Interactions with Fibrinogen Blood Plasma Protein: A Computational and Experimental Study |
title_sort | targeting beta-blocker drug–drug interactions with fibrinogen blood plasma protein: a computational and experimental study |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699576/ https://www.ncbi.nlm.nih.gov/pubmed/33228181 http://dx.doi.org/10.3390/molecules25225425 |
work_keys_str_mv | AT gonzalezdurruthymichael targetingbetablockerdrugdruginteractionswithfibrinogenbloodplasmaproteinacomputationalandexperimentalstudy AT concuriccardo targetingbetablockerdrugdruginteractionswithfibrinogenbloodplasmaproteinacomputationalandexperimentalstudy AT vendramelaurafosmari targetingbetablockerdrugdruginteractionswithfibrinogenbloodplasmaproteinacomputationalandexperimentalstudy AT zanellaivana targetingbetablockerdrugdruginteractionswithfibrinogenbloodplasmaproteinacomputationalandexperimentalstudy AT rusojuanm targetingbetablockerdrugdruginteractionswithfibrinogenbloodplasmaproteinacomputationalandexperimentalstudy AT cordeiromnataliads targetingbetablockerdrugdruginteractionswithfibrinogenbloodplasmaproteinacomputationalandexperimentalstudy |