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

2016 ◽  
Vol 18 (47) ◽  
pp. 32358-32368 ◽  
Author(s):  
Stefania Evoli ◽  
David L. Mobley ◽  
Rita Guzzi ◽  
Bruno Rizzuti
Keyword(s):  
Free Energy ◽  
Binding Sites ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Binding Modes ◽  
Large Protein ◽  
Multiple Binding Sites ◽  
Multiple Binding ◽  
Alchemical Free Energy ◽  
Absolute Binding Free Energy

Alchemical free energy methods can identify favored binding modes of a ligand within a large protein with multiple binding sites.

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

2016 ◽  
Author(s):  
Stefania Evoli ◽  
David L. Mobley ◽  
Rita Guzzi ◽  
Bruno Rizzuti
Keyword(s):  
Free Energy ◽  
Human Serum Albumin ◽  
Serum Albumin ◽  
Human Serum ◽  
Binding Sites ◽  
Free Energy Calculations ◽  
Binding Modes ◽  
Energy Calculations ◽  
Multiple Binding Sites ◽  
Multiple Binding

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.Graphical abstractFocusAlchemical free energy methods can identify favored binding modes of a ligand within a large protein with multiple binding sitesHighlightsHuman serum albumin binds the anti-inflammatory drug ibuprofen in multiple sitesAlchemical free energy calculations predicted favored binding modes of ibuprofenBound geometry, affinity and protonation state of the ligand were determinedSimulations identified a number of previously undetected binding sites for ibuprofenFree energy methods can be used to study large proteins with multiple binding sites

scholarly journals Challenges Encountered Applying Equilibrium and Non-Equilibrium Binding Free Energy Calculations

2020 ◽  
Author(s):  
Hannah Baumann ◽  
Vytautas Gapsys ◽  
Bert L. de Groot ◽  
David Mobley
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Side Chain ◽  
Future Research ◽  
Energy Calculations ◽  
Binding Free Energy Calculations ◽  
Sampling Problems ◽  
Alchemical Free Energy ◽  
Non Equilibrium

<div>Binding free energy calculations have become increasingly valuable to drive decision making in drug discovery projects. </div><div>However, among other issues, inadequate sampling can reduce accuracy, limiting the value of the technique.</div><div>In this paper we apply absolute binding free energy calculations to ligands binding to T4 lysozyme L99A and HSP90 using equilibrium and non-equilibrium approaches. We highlight sampling problems encountered in these systems, such as slow side chain rearrangements and slow changes of water placement upon ligand binding. These same types of challenges are likely to show up in other protein-ligand systems as well and we propose some strategies to diagnose and test for such problems in alchemical free energy calculations. We also explore similarities and differences in how the equilibrium and the non-equilibrium approaches handle these problems. Our results show the large amount of work still to be done to make free energy calculations robust and reliable and provide insight for future research in this area. </div>

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