Bioactive conformational generation of small molecules: A comparative analysis between force-field and multiple empirical criteria based methods

Background: Conformational sampling for small molecules plays an essential role in drug discovery research
pipeline. Based on multi-objective evolution algorithm (MOEA), we have developed a conformational generation
method called Cyndi in the previous study. In this work, in addition to Tripos force field in the previous version,
Cyndi was updated by incorporation of MMFF94 force field to assess the conformational energy more rationally.
With two force fields against a larger dataset of 742 bioactive conformations of small ligands extracted from PDB, a
comparative analysis was performed between pure force field based method (FFBM) and multiple empirical criteria
based method (MECBM) hybrided with different force fields.
Results: Our analysis reveals that incorporating multiple empirical rules can significantly improve the accuracy of
conformational generation. MECBM, which takes both empirical and force field criteria as the objective functions,
can reproduce about 54% (within 1Å RMSD) of the bioactive conformations in the 742-molecule testset, much
higher than that of pure force field method (FFBM, about 37%). On the other hand, MECBM achieved a more
complete and efficient sampling of the conformational space because the average size of unique conformations
ensemble per molecule is about 6 times larger than that of FFBM, while the time scale for conformational
generation is nearly the same as FFBM. Furthermore, as a complementary comparison study between the methods
with and without empirical biases, we also tested the performance of the three conformational generation
methods in MacroModel in combination with different force fields. Compared with the methods in MacroModel,
MECBM is more competitive in retrieving the bioactive conformations in light of accuracy but has much lower
computational cost.
Conclusions: By incorporating different energy terms with several empirical criteria, the MECBM method can
produce more reasonable conformational ensemble with high accuracy but approximately the same computational
cost in comparison with FFBM method. Our analysis also reveals that the performance of conformational
generation is irrelevant to the types of force field adopted in characterization of conformational accessibility.
Moreover, post energy minimization is not necessary and may even undermine the diversity of conformational
ensemble. All the results guide us to explore more empirical criteria like geometric restraints during the
conformational process, which may improve the performance of conformational generation in combination with
energetic accessibility, regardless of force field types adopted.