Alchemical Free Energy Calculations and Isothermal Titration Calorimetry Measurements of Aminoadamantanes Bound to the Closed State of Influenza A/M2TM
| Autor: | Antonios Kolocouris, Felix Kolarov, Kathrin Freudenberger, Paraskevi Gkeka, Zoe Cournia, Christos Liolios, Harris Ioannidis, Holger Gohlke, Christina Tzitzoglaki, Günter Gauglitz, Nadine Homeyer, Antonios Drakopoulos |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Rimantadine Entropy General Chemical Engineering Adamantane Calorimetry Molecular Dynamics Simulation Library and Information Sciences 010402 general chemistry medicine.disease_cause 01 natural sciences Viral Matrix Proteins 03 medical and health sciences chemistry.chemical_compound Protein Domains Tetramer Bennett acceptance ratio medicine Influenza A virus Humans Amino Acid Sequence Chemistry Cell Membrane Temperature Amantadine Stereoisomerism Isothermal titration calorimetry General Chemistry 0104 chemical sciences Computer Science Applications Crystallography 030104 developmental biology Protons Protein Binding medicine.drug |
| Zdroj: | Journal of Chemical Information and Modeling. 56:862-876 |
| ISSN: | 1549-960X 1549-9596 |
| DOI: | 10.1021/acs.jcim.6b00079 |
| Popis: | Adamantane derivatives, such as amantadine and rimantadine, have been reported to block the transmembrane domain (TM) of the M2 protein of influenza A virus (A/M2) but their clinical use has been discontinued due to evolved resistance in humans. Although experiments and simulations have provided adequate information about the binding interaction of amantadine or rimantadine to the M2 protein, methods for predicting binding affinities of whole series of M2 inhibitors have so far been scarcely applied. Such methods could assist in the development of novel potent inhibitors that overcome A/M2 resistance. Here we show that alchemical free energy calculations of ligand binding using the Bennett acceptance ratio (BAR) method are valuable for determining the relative binding potency of A/M2 inhibitors of the aminoadamantane type covering a binding affinity range of only ∼2 kcal mol(-1). Their binding affinities measured by isothermal titration calorimetry (ITC) against the A/M2TM tetramer from the Udorn strain in its closed form at pH 8 were used as experimental probes. The binding constants of rimantadine enantiomers against M2TMUdorn were measured for the first time and found to be equal. Two series of alchemical free energy calculations were performed using 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) lipids to mimic the membrane environment. A fair correlation was found for DPPC that was significantly improved using DMPC, which resembles more closely the DPC lipids used in the ITC experiments. This demonstrates that binding free energy calculations by the BAR approach can be used to predict relative binding affinities of aminoadamantane derivatives toward M2TM with good accuracy. |
| Databáze: | OpenAIRE |
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