Table Comparison between implementations. The performance on 4548 molecules in the Platinum dataset is shown. Time column shows the total time to process all molecules in second. RMSD column shows mean RMSD in Å. Bond, Angle, Torsion columns show mean error of each ( Å, • , • ). TFD column shows mean of the torsion fingerprint deviation . Success indicates the percent of predicted molecules whose InChIKey match that of the original molecule. RMSD and mean error are calculated over successful molecules. As compiled in Table the new implementation improves the stereochemical success rate from 76.3% to 93.9% while dramatically decreasing the time required by almost a factor of two (93.7 s to 54.8 s). The geometric accuracy increases very slightly, in part due to overall decreases in bond and dihedral/torsion errors. The differences between methods in RMSD, bond errors, angles and torsions are all statistically significant through analysis of variance (ANOVA) with p-values less than 1.0 × 10 -11 . Illustrated in Figure , the distribution of RMSD across the entire set of 4548 ligands is fairly similar between the original Open Babel implementation, RDKit ETKDG and the new implementation. The relatively high RMSD distribution is largely due to differences in conformations between the stochastic single pose considered here and an ensemble of diverse conformers needed to find low-RMSD geometries. In addition to the mean torsion angle error between the generated geometries and the experimental geometries, we computed the torsion fingerprint deviation (TFD) using RDKit, as an established metric for comparison of torsional errors. The metric ignores hydrogen atoms and minimizes effects of dihedral angles with multiple symmetric atoms. Both the mean torsion angle errors and TFD metrics in Table indicate evident differences in dihedral angles between generated geometries and experimental -the main cause for the relatively high observed RMSD. The fragment-based method is much faster than other methods because it can determine the coordinates of many atoms at once from the database. Compared to ETKDG, bond length errors and angle errors are generally better (e.g., 0.049 Åvs. 0.060 Å, respectively and 2.49 • vs. 2.87 • , respectively). On the other hand, RMSD and torsion errors are slightly worse than ETKDG, possibly because the current implementation does not consider torsion angle explicitly. Some stereo errors remain, likely because of issues with poor layout of some non-fragment bonds, resulting in incorrect stereochemistry.