Probe into the molecular mechanism of ibuprofen interaction with warfarin bound to human serum albumin in comparison to ascorbic and salicylic acids: Allosteric inhibition of anticoagulant release

Kalhor, H. R ; Sharif University of Technology | 2021

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  1. Type of Document: Article
  2. DOI: 10.1021/acs.jcim.1c00352
  3. Publisher: American Chemical Society , 2021
  4. Abstract:
  5. The release of anticoagulant drugs such as warfarin from human serum albumin (HSA) has been important not only mechanistically but also clinically for patients who take multiple drugs simultaneously. In this study, the role of some commonly used drugs, including s-ibuprofen, ascorbic acid, and salicylic acid, was investigated in the release of warfarin bound to HSA in silico. The effects of the aforementioned drugs on the HSA-warfarin complex were investigated with molecular dynamics (MD) simulations using two approaches; in the first perspective, molecular docking was used to model the interaction of each drug with the HSA-warfarin complex, and in the second approach, drugs were positioned randomly and distant from the binary complex (HSA-warfarin) in a physiologically relevant concentration. The results obtained from both approaches indicated that s-ibuprofen and ascorbic acid both displayed allosteric effects on the release of warfarin from HSA. Although ascorbic acid aided in warfarin release, leading to destabilization of HSA, ibuprofen demonstrated a stabilizing effect on releasing the anticoagulant drug through several noncovalent interactions, including hydrophobic, electrostatic, and hydrogen-bonding interactions with the protein. The calculated binding free energy and energy contribution of involved residues using the molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) method, along with root mean square deviation (RMSD) values, protein gyration, and free energy surface (FES) mapping of the protein, provided valuable details on the nature of the interactions of each drug on the release of warfarin from HSA. These results can provide important information on the mechanisms of anticoagulant release that has not been revealed in molecular details previously. ©
  6. Keywords:
  7. Binding energy ; Controlled drug delivery ; Drug interactions ; Free energy ; Hydrogen bonds ; Ions ; Molecular dynamics ; Physiological models ; Proteins ; Salicylic acid ; Targeted drug delivery ; Allosteric inhibition ; Anti-coagulant drugs ; Human serum albumins ; Hydrogen bonding interactions ; Molecular dynamics simulations ; Non-covalent interaction ; Poisson Boltzmann surface areas (PBSA) ; Root mean square deviations ; Ascorbic acid
  8. Source: Journal of Chemical Information and Modeling ; Volume 61, Issue 8 , 2021 , Pages 4045-4057 ; 15499596 (ISSN)
  9. URL: https://pubs.acs.org/doi/10.1021/acs.jcim.1c00352