Small-Molecule Conformer Generators: Evaluation of Traditional Methods and AI Models on High-Quality Data Sets
Zhe Wang, Haiyang Zhong, Jintu Zhang, Peichen Pan, Dong Wang, Huanxiang Liu, Xiaojun Yao, Tingjun Hou, Yu Kang
Abstract
Small-molecule conformer generation (SMCG) is an extremely important task in both ligand- and structure-based computer-aided drug design, especially during the hit discovery phase. Recently, a multitude of artificial intelligence (AI) models tailored for SMCG have emerged. Despite developers typically furnishing performance evaluation data upon releasing their AI models, a comprehensive and equitable performance comparison between AI models and conventional methods is still lacking. In this study, we curated a new benchmarking data set comprising 3354 high-quality ligand bioactive conformations. Subsequently, we conducted a systematic assessment of the performance of four widely adopted traditional methods (i.e., ConfGenX, Conformator, OMEGA, and RDKit ETKDG) and five AI models (i.e., ConfGF, DMCG, GeoDiff, GeoMol, and torsional diffusion) in the tasks of reproducing bioactive and low-energy conformations of small molecules. In the former task, the AI models have no advantage, particularly with a maximum ensemble size of 1. Even the best-performing AI model GeoMol is still worse than any of the tested traditional methods. Conversely, in the latter task, the torsional diffusion model shows obvious advantages, surpassing the best-performing traditional method ConfGenX by 26.09 and 12.97% on the COV-R and COV-P metrics, respectively. Furthermore, the influence of force field-based fine-tuning on the quality of the generated conformers was also discussed. Finally, a user-friendly Web server called fastSMCG was developed to enable researchers to rapidly and flexibly generate small-molecule conformers using both traditional and AI methods. We anticipate that our work will offer valuable practical assistance to the scientific community in this field.