Targeting Beta-Blocker Drug–Drug Interactions with Fibrinogen Blood Plasma Protein: A Computational and Experimental Study
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Título: | Targeting Beta-Blocker Drug–Drug Interactions with Fibrinogen Blood Plasma Protein: A Computational and Experimental Study |
Autor/a: | González Durruthy, Michael Concu, Riccardo Osmari Vendrame, Laura F. Zanella, Ivana Ruso Beiras, Juan Manuel Cordeiro, M. Natália D. S. |
Centro/Departamento: | Universidade de Santiago de Compostela. Departamento de Física Aplicada |
Palabras chave: | Drug–drug interactions | Beta-blocker drugs | Polypharmacology | Molecular docking | DFT | Ultrasound measurements | |
Data: | 2020 |
Editor: | MDPI |
Cita bibliográfica: | González-Durruthy, M.; Concu, R.; Vendrame, L.F.O.; Zanella, I.; Ruso, J.M.; Cordeiro, M.N.D.S. Targeting Beta-Blocker Drug–Drug Interactions with Fibrinogen Blood Plasma Protein: A Computational and Experimental Study. Molecules 2020, 25, 5425 |
Resumo: | 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 |
Versión do editor: | https://doi.org/10.3390/molecules25225425 |
URI: | http://hdl.handle.net/10347/24032 |
DOI: | 10.3390/molecules25225425 |
E-ISSN: | 1420-3049 |
Dereitos: | © 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/). Atribución 4.0 Internacional |
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