Scaffold Hopping Transformations Using Auxiliary Restraints for Calculating Accurate Relative Binding Free Energies

In silico screening of drug–target interactions
is a key part of the drug discovery process. Changes in the drug scaffold
via contraction or expansion of rings, the breaking of rings, and
the introduction of cyclic structures from acyclic structures are
commonly applied by medicinal chemists to improve binding affinity
and enhance favorable properties of candidate compounds. These processes,
commonly referred to as scaffold hopping, are challenging to model
computationally. Although relative binding free energy (RBFE) calculations
have shown success in predicting binding affinity changes caused by
perturbing R-groups attached to a common scaffold, applications of
RBFE calculations to modeling scaffold hopping are relatively limited.
Scaffold hopping inevitably involves breaking and forming bond interactions
of quadratic functional forms, which is highly challenging. A novel
method for handling ring opening/closure/contraction/expansion and
linker contraction/expansion is presented here. To the best of our
knowledge, RBFE calculations on linker contraction/expansion have
not been previously reported. The method uses auxiliary restraints
to hold the atoms at the ends of a bond in place during the breaking
and forming of the bonds. The broad applicability of the method was
demonstrated by examining perturbations involving small-molecule macrocycles
and mutations of proline in proteins. High accuracy was obtained using
the method for most of the perturbations studied. The rigor of the
method was isolated from the force field by validating the method
using relative and absolute hydration free energy calculations compared
to standard simulation results. Unlike other methods that rely on
λ-dependent functional forms for bond interactions, the method
presented here can be employed using modern molecular dynamics software
without modification of codes or force field functions.