Empirical scoring functions based on either molecular force fields or
cheminformatics descriptors are widely used, in conjunction with molecular
docking, during the early stages of drug discovery to predict potency and
binding affinity of a drug-like molecule to a given target. These models
require expert-level knowledge of physical chemistry and biology to be encoded
as hand-tuned parameters or features rather than allowing the underlying model
to select features in a data-driven procedure. Here, we develop a general
3-dimensional spatial convolution operation for learning atomic-level chemical
interactions directly from atomic coordinates and demonstrate its application
to structure-based bioactivity prediction. The atomic convolutional neural
network is trained to predict the experimentally determined binding affinity of
a protein-ligand complex by direct calculation of the energy associated with
the complex, protein, and ligand given the crystal structure of the binding
pose. Non-covalent interactions present in the complex that are absent in the
protein-ligand sub-structures are identified and the model learns the
interaction strength associated with these features. We test our model by
predicting the binding free energy of a subset of protein-ligand complexes
found in the PDBBind dataset and compare with state-of-the-art cheminformatics
and machine learning-based approaches. We find that all methods achieve
experimental accuracy and that atomic convolutional networks either outperform
or perform competitively with the cheminformatics based methods. Unlike all
previous protein-ligand prediction systems, atomic convolutional networks are
end-to-end and fully-differentiable. They represent a new data-driven,
physics-based deep learning model paradigm that offers a strong foundation for
future improvements in structure-based bioactivity prediction.

本文提出了一种基于原子层次化学相互作用的空间卷积神经网络来预测蛋白质 - 配体复合物的生物活性，并展示了其优于化学信息处理方法的实验结果。