Large-Scale Analysis of Bioactive Ligand Conformational Strain Energy by <i>Ab Initio</i> Calculation

Ligand conformational strain energy
(LCSE) plays an important role
in virtual screening and lead optimization. While various studies
have provided insights into LCSE for small-molecule ligands in the
Protein Data Bank (PDB), conclusions are inconsistent mainly due to
small datasets, poor quality control of crystal structures, and molecular
mechanics (MM) or low-level quantum mechanics (QM) calculations. Here,
we built a high-quality dataset (LigBoundConf) of 8145 ligand-bound
conformations from PDB crystal structures and calculated LCSE at the
M062X-D3/ma-TZVPP (SMD)//M062X-D3/def2-SVP­(SMD) level for each case
in the dataset. The mean/median LCSE is 4.6/3.7 kcal/mol for 6672
successfully calculated cases, which is significantly lower than the
estimates based on molecular mechanics in many previous analyses.
Especially, when removing ligands with nonaromatic ring(s) that are
prone to have large LCSEs due to electron density overfitting, the
mean/median LCSE was reduced to 3.3/2.5 kcal/mol. We further reveal
that LCSE is correlated with several ligand properties, including
formal atomic charge, molecular weight, number of rotatable bonds,
and number of hydrogen-bond donors and acceptors. In addition, our
results show that although summation of torsion strains is a good
approximation of LCSE for most cases, for a small fraction (about
6%) of our dataset, it underestimates LCSEs if ligands could form
nonlocal intramolecular interactions in the unbound state. Taken together,
our work provides a comprehensive profile of LCSE for ligands in PDB,
which could help ligand conformation generation, ligand docking pose
evaluation, and lead optimization.