3 research outputs found
Interpreting Thermodynamic Profiles of Aminoadamantane Compounds Inhibiting the M2 Proton Channel of Influenza A by Free Energy Calculations
The development of novel anti-influenza
drugs is of great importance
because of the capability of influenza viruses to occasionally cross
interspecies barriers and to rapidly mutate. One class of anti-influenza
agents, aminoadamantanes, including the drugs amantadine and rimantadine
now widely abandoned due to virus resistance, bind to and block the
pore of the transmembrane domain of the M2 proton channel (M2TM) of
influenza A. Here, we present one of the still rare studies that interprets
thermodynamic profiles from isothermal titration calorimetry (ITC)
experiments in terms of individual energy contributions to binding,
calculated by the computationally inexpensive implicit solvent/implicit
membrane molecular mechanics Poisson–Boltzmann surface area
(MM-PBSA) approach, for aminoadamantane compounds binding to M2TM
of the avian “Weybridge” strain. For all eight pairs
of aminoadamantane compounds considered, the trend of the predicted
relative binding free energies and their individual components, effective
binding energies and changes in the configurational entropy, agrees
with experimental measures (ΔΔ<i>G</i>, ΔΔ<i>H</i>, <i>T</i>ΔΔ<i>S</i>) in
88, 88, and 50% of the cases. In addition, information yielded by
the MM-PBSA approach about determinants of binding goes beyond that
available in component quantities (Δ<i>H</i>, Δ<i>S</i>) from ITC measurements. We demonstrate how one can make
use of such information to link thermodynamic profiles from ITC with
structural causes on the ligand side and, ultimately, to guide decision
making in lead optimization in a prospective manner, which results
in an aminoadamantane derivative with improved binding affinity against
M2TM<sub>Weybridge</sub>
Binding and Proton Blockage by Amantadine Variants of the Influenza M2<sub>WT</sub> and M2<sub>S31N</sub> Explained
While
aminoadamantanes are well-established inhibitors of the influenza
A M2 proton channel, the mechanisms by which they are rendered ineffective
against M2<sub>S31N</sub> are unclear. Solid state NMR, isothermal
titration calorimetry, electrophysiology, antiviral assays, and molecular
dynamics simulations suggest stronger binding interactions for aminoadamantanes
to M2<sub>WT</sub> compared to negligible or weak binding to M2<sub>S31N</sub>. This is due to reshaping of the M2 pore when N31 is present,
which, in contrast to wild-type (WT), leads (A) to the loss of the
V27 pocket for the adamantyl cage and to a predominant orientation
of the ligand’s ammonium group toward the N-terminus and (B)
to the lack of a helical kink upon ligand binding. The kink, which
reduces the tilt of the C-terminal helical domain relative to the
bilayer normal, includes the W41 primary gate for proton conductance
and may prevent the gate from opening, representing an alternative
view for how these drugs prevent proton conductance
Binding and Proton Blockage by Amantadine Variants of the Influenza M2<sub>WT</sub> and M2<sub>S31N</sub> Explained
While
aminoadamantanes are well-established inhibitors of the influenza
A M2 proton channel, the mechanisms by which they are rendered ineffective
against M2<sub>S31N</sub> are unclear. Solid state NMR, isothermal
titration calorimetry, electrophysiology, antiviral assays, and molecular
dynamics simulations suggest stronger binding interactions for aminoadamantanes
to M2<sub>WT</sub> compared to negligible or weak binding to M2<sub>S31N</sub>. This is due to reshaping of the M2 pore when N31 is present,
which, in contrast to wild-type (WT), leads (A) to the loss of the
V27 pocket for the adamantyl cage and to a predominant orientation
of the ligand’s ammonium group toward the N-terminus and (B)
to the lack of a helical kink upon ligand binding. The kink, which
reduces the tilt of the C-terminal helical domain relative to the
bilayer normal, includes the W41 primary gate for proton conductance
and may prevent the gate from opening, representing an alternative
view for how these drugs prevent proton conductance