Pretraining graph transformers with atom-in-a-molecule quantum properties for improved ADMET modeling

Abstract

We evaluate the impact of pretraining Graph Transformer architectures on atom-level quantum-mechanical features for the modeling of absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of drug-like compounds. We compare this pretraining strategy with two others: one based on molecular quantum properties (specifically the HOMO-LUMO gap) and one using a self-supervised atom masking technique. After fine-tuning on Therapeutic Data Commons ADMET datasets, we evaluate the performance improvement in the different models observing that models pretrained with atomic quantum mechanical properties produce in general better results. We then analyze the latent representations and observe that the supervised strategies preserve the pretraining information after fine-tuning and that different pretrainings produce different trends in latent expressivity across layers. Furthermore, we find that models pretrained on atomic quantum mechanical properties capture more low-frequency Laplacian eigenmodes of the input graph via the attention weights and produce better representations of atomic environments within the molecule. Application of the analysis to a much larger non-public dataset for microsomal clearance illustrates generalizability of the studied indicators. In this case the performances of the models are in accordance with the representation analysis and highlight, especially for the case of masking pretraining and atom-level quantum property pretraining, how model types with similar performance on public benchmarks can have different performances on large scale pharmaceutical data.

Scientific contribution

We systematically compared three different data type/methodologies for pretraining molecular Graphormer with the purpose of modeling ADMET properties as downstream tasks. The learned representations from differently pretrained models were analyzed in addition to comparison of downstream task performances that have been typically reported in similar works. Such examination methodologies, including a newly introduced analysis of Graphormer’s Attention Rollout Matrix, can guide pretraining strategy selection, as corroborated by a performance evaluation on a larger internal dataset.