posted on 2023-11-09, 15:05authored byMartin Vögele, Bin W. Zhang, Jonas Kaindl, Lingle Wang
For an effective drug, strong binding
to the target protein is
a prerequisite, but it is not enough. To produce a particular functional
response, drugs need to either block the proteins’ functions
or modulate their activities by changing their conformational equilibrium.
The binding free energy of a compound to its target is routinely calculated,
but the timescales for the protein conformational changes are prohibitively
long to be efficiently modeled via physics-based simulations. Thermodynamic
principles suggest that the binding free energies of the ligands with
different receptor conformations may infer their efficacy. However,
this hypothesis has not been thoroughly validated. We present an actionable
protocol and a comprehensive study to show that binding thermodynamics
provides a strong predictor of the efficacy of a ligand. We apply
the absolute binding free energy perturbation method to ligands bound
to active and inactive states of eight G protein-coupled receptors
and a nuclear receptor and then compare the resulting binding free
energies. We find that carefully designed restraints are often necessary
to efficiently model the corresponding conformational ensembles for
each state. Our method achieves unprecedented performance in classifying
ligands as agonists or antagonists across the various investigated
receptors, all of which are important drug targets.