Using attribution to decode binding mechanism in neural network models for chemistry
Abstract
Deep neural networks have achieved state of the art accuracy at classifying molecules with respect to whether they bind to specific protein targets. A key breakthrough would occur if these models could reveal the fragment pharmacophores that are causally involved in binding. Extracting chemical details of binding from the networks could potentially lead to scientific discoveries about the mechanisms of drug actions. But doing so requires shining light into the black box that is the trained neural network model, a task that has proved difficult across many domains. Here we show how the binding mechanism learned by deep neural network models can be interrogated, using a recently described attribution method. We first work with carefully constructed synthetic datasets, in which the 'fragment logic' of binding is fully known. We find that networks that achieve perfect accuracy on held out test datasets still learn spurious correlations due to biases in the datasets, and we are able to exploit this non-robustness to construct adversarial examples that fool the model. The dataset bias makes these models unreliable for accurately revealing information about the mechanisms of protein-ligand binding. In light of our findings, we prescribe a test that checks for dataset bias given a hypothesis. If the test fails, it indicates that either the model must be simplified or regularized and/or that the training dataset requires augmentation.
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