Torsional Energy Barriers of Biaryls Could Be Predicted by Electron Richness/Deficiency of Aromatic Rings; Advancement of Molecular Mechanics toward Atom-Type Independence

Biaryl
molecules are ubiquitous pharmacophores found in natural
products and pharmaceuticals. In spite of this, existing molecular
mechanics force fields are unable to accurately reproduce their torsional
energy profiles, except for a few well-parametrized cases. This effectively
limits the ability of structure-based drug design methods to correctly
identify hits involving biaryls with confidence (e.g., during virtual
screening, employing docking and/or molecular dynamics simulations).
Continuing in our endeavor to quantify organic chemistry principles,
we showed that the torsional energy profile of biaryl compounds could
be computed on-the-fly based on the electron richness/deficiency of
the aromatic rings. This method, called H-TEQ 4.0, was developed using
a set of 131 biaryls. It was subsequently validated on a separate
set of 100 diverse biaryls, including multisubstituted, bicyclic and
tricyclic druglike molecules, and produced an average root-mean-square
error (RMSE) of 0.95 kcal·mol–1. For comparison,
GAFF2 produced an RMSE of 3.88 kcal·mol–1,
owing to problems associated with the transferability of torsion parameters.
The success of H-TEQ 4.0 provided further evidence that force fields
could transition to become atom-type independent, providing that the
correct chemical principles are used. Overall, this method solved
the problem of transferability of biaryl torsion parameters, while
simultaneously improving the overall accuracy of the force field.