A Relative Binding Free Energy Framework for Structurally Dissimilar Molecules

Relative binding free energy (RBFE) calculations, widely
used to
predict the potencies of congeneric small molecules binding to a protein
receptor, can greatly increase the efficiency of the hit-to-lead and
lead optimization stages of the drug discovery process. Traditional
RBFE methods, however, cannot be easily applied to small molecules
lacking a common core or binding mode, precluding their use in a challenging
but crucial component of many drug discovery campaigns. In principle,
an absolute binding free energy (ABFE) method can be applied to such
molecules, but ABFE often suffers from high computational cost and
poor statistical convergence due to the large amount of additional
sampling required when compared to RBFE. Here, we introduce core-hopping
binding free energy (CBFE) calculations, a computationally efficient
framework for the accurate determination of relative binding free
energies between small molecules with different cores, leveraging
several recently developed techniques such as Alchemical Enhanced
Sampling (ACES) with optimized transformation pathways and flexible
λ-spacing, as well as λ-dependent Boresch restraints.
We benchmark the performance of CBFE across 4 protein systems consisting
of 56 small molecules, and find that the results are consistent with
RBFE for a congeneric series of ligands and offer considerable improvement
in computational cost and precision relative to ABFE results for a
series of small molecules with diverse cores and binding modes. All
CBFE-related developments are fully implemented in the GPU-accelerated
AMBER free energy module (pmemd.cuda) and are available as part of
the latest official AMBER release.