Multiple binding modes of ibuprofen in human serum albumin identified by absolute binding free energy calculations

Handle URI:
http://hdl.handle.net/10754/622898
Title:
Multiple binding modes of ibuprofen in human serum albumin identified by absolute binding free energy calculations
Authors:
Evoli, Stefania; Mobley, David L.; Guzzi, Rita; Rizzuti, Bruno
Abstract:
Human serum albumin possesses multiple binding sites and transports a wide range of ligands that include the anti-inflammatory drug ibuprofen. A complete map of the binding sites of ibuprofen in albumin is difficult to obtain in traditional experiments, because of the structural adaptability of this protein in accommodating small ligands. In this work, we provide a set of predictions covering the geometry, affinity of binding and protonation state for the pharmaceutically most active form (S-isomer) of ibuprofen to albumin, by using absolute binding free energy calculations in combination with classical molecular dynamics (MD) simulations and molecular docking. The most favorable binding modes correctly reproduce several experimentally identified binding locations, which include the two Sudlow's drug sites (DS2 and DS1) and the fatty acid binding sites 6 and 2 (FA6 and FA2). Previously unknown details of the binding conformations were revealed for some of them, and formerly undetected binding modes were found in other protein sites. The calculated binding affinities exhibit trends which seem to agree with the available experimental data, and drastically degrade when the ligand is modeled in a protonated (neutral) state, indicating that ibuprofen associates with albumin preferentially in its charged form. These findings provide a detailed description of the binding of ibuprofen, help to explain a wide range of results reported in the literature in the last decades, and demonstrate the possibility of using simulation methods to predict ligand binding to albumin.
KAUST Department:
KAUST Catalysis Center (KCC)
Citation:
Evoli S, Mobley DL, Guzzi R, Rizzuti B (2016) Multiple binding modes of ibuprofen in human serum albumin identified by absolute binding free energy calculations. Phys Chem Chem Phys 18: 32358–32368. Available: http://dx.doi.org/10.1039/c6cp05680f.
Publisher:
Royal Society of Chemistry (RSC)
Journal:
Phys. Chem. Chem. Phys.
Issue Date:
10-Nov-2016
DOI:
10.1039/c6cp05680f
Type:
Article
ISSN:
1463-9076; 1463-9084
Sponsors:
DLM appreciates financial support from the National Institutes of Health (1R01GM108889-01).
Additional Links:
http://pubs.rsc.org/en/Content/ArticleLanding/2016/CP/C6CP05680F#!divAbstract
Appears in Collections:
Articles; KAUST Catalysis Center (KCC)

Full metadata record

DC FieldValue Language
dc.contributor.authorEvoli, Stefaniaen
dc.contributor.authorMobley, David L.en
dc.contributor.authorGuzzi, Ritaen
dc.contributor.authorRizzuti, Brunoen
dc.date.accessioned2017-02-15T08:32:15Z-
dc.date.available2017-02-15T08:32:15Z-
dc.date.issued2016-11-10en
dc.identifier.citationEvoli S, Mobley DL, Guzzi R, Rizzuti B (2016) Multiple binding modes of ibuprofen in human serum albumin identified by absolute binding free energy calculations. Phys Chem Chem Phys 18: 32358–32368. Available: http://dx.doi.org/10.1039/c6cp05680f.en
dc.identifier.issn1463-9076en
dc.identifier.issn1463-9084en
dc.identifier.doi10.1039/c6cp05680fen
dc.identifier.urihttp://hdl.handle.net/10754/622898-
dc.description.abstractHuman serum albumin possesses multiple binding sites and transports a wide range of ligands that include the anti-inflammatory drug ibuprofen. A complete map of the binding sites of ibuprofen in albumin is difficult to obtain in traditional experiments, because of the structural adaptability of this protein in accommodating small ligands. In this work, we provide a set of predictions covering the geometry, affinity of binding and protonation state for the pharmaceutically most active form (S-isomer) of ibuprofen to albumin, by using absolute binding free energy calculations in combination with classical molecular dynamics (MD) simulations and molecular docking. The most favorable binding modes correctly reproduce several experimentally identified binding locations, which include the two Sudlow's drug sites (DS2 and DS1) and the fatty acid binding sites 6 and 2 (FA6 and FA2). Previously unknown details of the binding conformations were revealed for some of them, and formerly undetected binding modes were found in other protein sites. The calculated binding affinities exhibit trends which seem to agree with the available experimental data, and drastically degrade when the ligand is modeled in a protonated (neutral) state, indicating that ibuprofen associates with albumin preferentially in its charged form. These findings provide a detailed description of the binding of ibuprofen, help to explain a wide range of results reported in the literature in the last decades, and demonstrate the possibility of using simulation methods to predict ligand binding to albumin.en
dc.description.sponsorshipDLM appreciates financial support from the National Institutes of Health (1R01GM108889-01).en
dc.publisherRoyal Society of Chemistry (RSC)en
dc.relation.urlhttp://pubs.rsc.org/en/Content/ArticleLanding/2016/CP/C6CP05680F#!divAbstracten
dc.titleMultiple binding modes of ibuprofen in human serum albumin identified by absolute binding free energy calculationsen
dc.typeArticleen
dc.contributor.departmentKAUST Catalysis Center (KCC)en
dc.identifier.journalPhys. Chem. Chem. Phys.en
dc.contributor.institutionDepartment of Physics, University of Calabria, 87036 Rende, Italyen
dc.contributor.institutionDepartments of Pharmaceutical Sciences and Chemistry, University of California, Irvine, USAen
dc.contributor.institutionCNISM Unit, University of Calabria, 87036 Rende, Italyen
dc.contributor.institutionCNR-NANOTEC, Licryl-UOS Cosenza and CEMIF.Cal, Department of Physics, University of Calabria, 87036 Rende, Italyen
kaust.authorEvoli, Stefaniaen
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