1 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>