Benchmark of 3D conformer generation and molecular property calculation for medium-sized molecules

Medium-sized molecules have attracted significant attention as new chemical modalities. In this study, we compared the performances of three methods of 3D structure generation for medium-sized molecules using free and commercial software. The benchmark dataset consisted of 2131 protein-binding ligands with molecular weights greater than 600, which were selected from the Protein Data Bank (PDB). When selecting the smallest root mean square deviation between the generated 3D conformers and the PDB ligand structures, 43% of the conformations determined with the software CORINA were within 1 angstrom, followed by 10% from OMEGA and 5% from RDKit. According to our results, comparing the polar solvent-accessible surface area (PSA) and normalized principal moment of inertia ratio (NPR) among the three methods, 83% of the conformers generated with CORINA were within 20 in PSA, and 53% of the conformers from CORINA were within 0.05 in the NPR1 and NPR2 spaces. Thus, we concluded that CORINA has the highest performance in terms of efficient conformer generation. We also examined 3D descriptor calculation using Mordred, which is a free descriptor computation tool. The results showed that OMEGA-generated conformers exhibited the highest success rate, indicating that OMEGA is a suitable conformer generation tool for various 3D descriptors. Our results could contribute to the selection of conformation generators for the rapid construction of various predictive models for medium-sized molecules and can be shared with the research community for further validation.