Dataset Information

Targeting Beta-Blocker Drug-Drug Interactions with Fibrinogen Blood Plasma Protein: A Computational and Experimental Study.

ABSTRACT: 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.

SUBMITTER: Gonzalez-Durruthy M

PROVIDER: S-EPMC7699576 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Targeting Beta-Blocker Drug-Drug Interactions with Fibrinogen Blood Plasma Protein: A Computational and Experimental Study.

González-Durruthy Michael M Concu Riccardo R Vendrame Laura F Osmari LFO Zanella Ivana I Ruso Juan M JM Cordeiro M Natália D S MNDS

Molecules (Basel, Switzerland) 20201119 22

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 tot ...[more]

PMID: 33228181

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Project description:Norovirus (NoV) is the major pathogen causing the outbreaks of the viral gastroenteritis across the world. Among the various genotypes of NoV, GII.4 is the most predominant over the past decades. GII.4 NoVs interact with the histo-blood group antigens (HBGAs) to invade the host cell, and it is believed that the receptor HBGAs may play important roles in selecting the predominate variants by the nature during the evolution of GII.4 NoVs. However, the evolution-induced changes in the HBGA-binding affinity for the GII.4 NoV variants and the mechanism behind the evolution of the NoV-HBGA interactions remain elusive. In the present work, the virus-like particles (VLPs) of the representative GII.4 NoV stains epidemic in the past decades were expressed by using the Hansenula polymorpha yeast expression platform constructed by our laboratory, and then the enzyme linked immunosorbent assay (ELISA)-based HBGA-binding assays as well as the molecular dynamics (MD) simulations combined with the molecular mechanics/generalized born surface area (MMGBSA) calculations were performed to investigate the interactions between various GII.4 strains and different types of HBGAs. The HBGA-binding assays show that for all the studied types of HBGAs, the evolution of GII.4 NoVs results in the increased NoV-HBGA binding affinities, where the early epidemic strains have the lower binding activity and the newly epidemic strains exhibit relative stronger binding intensity. Based on the MD simulation and MMGBSA calculation results, a physical mechanism that accounts for the increased HBGA-binding affinity was proposed. The evolution-involved residue mutations cause the conformational rearrangements of loop-2 (residues 390-396), which result in the narrowing of the receptor-binding pocket and thus tighten the binding of the receptor HBGAs. Our experimental and computational studies are helpful for better understanding the mechanism behind the evolution-induced increasing of HBGA-binding affinity, which may provide useful information for the drug and vaccine designs against GII.4 NoVs.

Dataset Information

Targeting Beta-Blocker Drug-Drug Interactions with Fibrinogen Blood Plasma Protein: A Computational and Experimental Study.

Publications

Targeting Beta-Blocker Drug-Drug Interactions with Fibrinogen Blood Plasma Protein: A Computational and Experimental Study.

Similar Datasets

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