TY - JOUR
T1 - Affinity of Rimantadine Enantiomers against Influenza A/M2 Protein Revisited
AU - Drakopoulos, Antonios
AU - Tzitzoglaki, Christina
AU - Ma, Chulong
AU - Freudenberger, Kathrin
AU - Hoffmann, Anja
AU - Hu, Yanmei
AU - Gauglitz, Günter
AU - Schmidtke, Michaela
AU - Wang, Jun
AU - Kolocouris, Antonios
N1 - Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/2/9
Y1 - 2017/2/9
N2 - Recent findings from solid state NMR (ssNMR) studies suggested that the (R)-enantiomer of rimantadine binds to the full M2 protein with higher affinity than the (S)-enantiomer. Intrigued by these findings, we applied functional assays, such as antiviral assay and electrophysiology (EP), to evaluate the binding affinity of rimantadine enantiomers to the M2 protein channel. Unexpectedly, no significant difference was found between the two enantiomers. Our experimental data based on the full M2 protein function were further supported by alchemical free energy calculations and isothermal titration calorimetry (ITC) allowing an evaluation of the binding affinity of rimantadine enantiomers to the M2TM pore. Both enantiomers have similar channel blockage, affinity, and antiviral potency.
AB - Recent findings from solid state NMR (ssNMR) studies suggested that the (R)-enantiomer of rimantadine binds to the full M2 protein with higher affinity than the (S)-enantiomer. Intrigued by these findings, we applied functional assays, such as antiviral assay and electrophysiology (EP), to evaluate the binding affinity of rimantadine enantiomers to the M2 protein channel. Unexpectedly, no significant difference was found between the two enantiomers. Our experimental data based on the full M2 protein function were further supported by alchemical free energy calculations and isothermal titration calorimetry (ITC) allowing an evaluation of the binding affinity of rimantadine enantiomers to the M2TM pore. Both enantiomers have similar channel blockage, affinity, and antiviral potency.
KW - Bennett’s acceptance ratio
KW - Rimantadine enantiomers
KW - antiviral assay
KW - electrophysiology
KW - free energy perturbation
KW - influenza M2 pore
KW - isothermal titration calorimetry
KW - membrane protein
KW - synthesis
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U2 - 10.1021/acsmedchemlett.6b00311
DO - 10.1021/acsmedchemlett.6b00311
M3 - Article
AN - SCOPUS:85013828925
SN - 1948-5875
VL - 8
SP - 145
EP - 150
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 2
ER -