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...
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| Format: | Article |
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MDPI AG
2020-11-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/22/5425 |
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| author | Michael González-Durruthy Riccardo Concu Laura F. Osmari Vendrame Ivana Zanella Juan M. Ruso M. Natália D. S. Cordeiro |
| author_facet | Michael González-Durruthy Riccardo Concu Laura F. Osmari Vendrame Ivana Zanella Juan M. Ruso M. Natália D. S. Cordeiro |
| author_sort | Michael González-Durruthy |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T14:44:21Z |
| format | Article |
| id | doaj.art-e51b340f700049459ebe22a74631bc7f |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T14:44:21Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-e51b340f700049459ebe22a74631bc7f2023-11-20T21:35:35ZengMDPI AGMolecules1420-30492020-11-012522542510.3390/molecules25225425Targeting Beta-Blocker Drug–Drug Interactions with Fibrinogen Blood Plasma Protein: A Computational and Experimental StudyMichael González-Durruthy0Riccardo Concu1Laura F. Osmari Vendrame2Ivana Zanella3Juan M. Ruso4M. Natália D. S. Cordeiro5LAQV-REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, PortugalLAQV-REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, PortugalPost-Graduate Program in Nanoscience, Franciscana University (UFN), Santa Maria 97010-032, RS, BrazilPost-Graduate Program in Nanoscience, Franciscana University (UFN), Santa Maria 97010-032, RS, BrazilSoft Matter and Molecular Biophysics Group, Department of Applied Physics, University of Santiago de Compostela, 15782 Santiago de Compostela, SpainLAQV-REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, PortugalIn 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.https://www.mdpi.com/1420-3049/25/22/5425drug–drug interactionsbeta-blocker drugspolypharmacologymolecular dockingDFTultrasound measurements |
| spellingShingle | Michael González-Durruthy Riccardo Concu Laura F. Osmari Vendrame Ivana Zanella Juan M. Ruso M. Natália D. S. Cordeiro Targeting Beta-Blocker Drug–Drug Interactions with Fibrinogen Blood Plasma Protein: A Computational and Experimental Study Molecules drug–drug interactions beta-blocker drugs polypharmacology molecular docking DFT ultrasound measurements |
| 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 | drug–drug interactions beta-blocker drugs polypharmacology molecular docking DFT ultrasound measurements |
| url | https://www.mdpi.com/1420-3049/25/22/5425 |
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