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...

Descripción completa

Detalles Bibliográficos
Autores principales: González-Durruthy, Michael, Concu, Riccardo, Vendrame, Laura F. Osmari, Zanella, Ivana, Ruso, Juan M., Cordeiro, M. Natália D. S.
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