Artificial Intelligence for Predicting Small-Molecule Bioactive Conformations

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Abstract
Precise prediction of bioactive conformations represents a central challenge in drug discovery. Traditional computational methods often rely on the assumption that the global minimum energy state corresponds to the bioactive conformation─a hypothesis with inherent limitations. Data-driven artificial intelligence (AI) models have revolutionized research methodologies in this domain. By learning the implicit probability distributions of conformations, AI demonstrates the potential to achieve high-precision predictions of bioactive structures. This review systematically surveys technical advancements ranging from geometric regression to generative and conditional generative models, analyzing their effectiveness in benchmarks and de novo design experiments. We deeply explore critical challenges, including data sparsity, sampling efficiency, generation capability, and interpretability. Finally, we provide an outlook on bridging the gap from "structural prediction" to "functional design" through the construction of dynamic data sets, the development of efficient algorithms, and the implementation of human-in-the-loop collaborative decision-making systems.
Funding Information
  • National Natural Science Foundation of China (81903439)

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