Predicting the pharmacological activity, toxicity, and pharmacokinetic properties of molecules is a central task in drug discovery. Existing machine learning methods are transferred from one resource rich molecular property to another data scarce property in the same scaffold dataset. However, existing models may produce fragile and highly uncertain predictions for new scaffold molecules. And these models were tested on different benchmarks, which seriously affected the quality of their evaluation results. In this article, we introduce Meta-MolNet, a collection of data benchmark and algorithms, which is a standard benchmark platform for measuring model generalization and uncertainty quantification capabilities. Meta-MolNet manages a wide range of molecular datasets with high ratio of molecules/scaffolds, which often leads to more difficult data shift and generalization problems. Furthermore, we propose a graph attention network based on cross-domain meta-learning, Meta-GAT, which uses bilevel optimization to learn meta-knowledge from the scaffold family molecular dataset in the source domain. Meta-GAT benefits from meta-knowledge that reduces the requirement of sample complexity to enable reliable predictions of new scaffold molecules in the target domain through internal iteration of a few examples. We evaluate existing methods as baselines for the community, and the Meta-MolNet benchmark demonstrates the effectiveness of measuring the proposed algorithm in domain generalization and uncertainty quantification. Extensive experiments demonstrate that the Meta-GAT model has state-of-the-art domain generalization performance and robustly estimates uncertainty under few examples constraints. By publishing AI-ready data, evaluation frameworks, and baseline results, we hope to see the Meta-MolNet suite become a comprehensive resource for the AI-assisted drug discovery community. Meta-MolNet is freely accessible at https://github.com/lol88/Meta-MolNet.

Inductive bias in machine learning (ML) is the set of assumptions describing how a model makes predictions. Different ML-based methods for protein-ligand binding affinity (PLA) prediction have different inductive biases, leading to different levels of generalization capability and interpretability. Intuitively, the inductive bias of an ML-based model for PLA prediction should fit in with biological mechanisms relevant for binding to achieve good predictions with meaningful reasons. To this end, we propose an interaction-based inductive bias to restrict neural networks to functions relevant for binding with two assumptions: 1) A protein-ligand complex can be naturally expressed as a heterogeneous graph with covalent and non-covalent interactions; 2) The predicted PLA is the sum of pairwise atom-atom affinities determined by non-covalent interactions. The interaction-based inductive bias is embodied by an explainable heterogeneous interaction graph neural network (EHIGN) for explicitly modeling pairwise atom-atom interactions to predict PLA from 3D structures. Extensive experiments demonstrate that EHIGN achieves better generalization capability than other state-of-the-art ML-based baselines in PLA prediction and structure-based virtual screening. More importantly, comprehensive analyses of distance-affinity, pose-affinity, and substructure-affinity relations suggest that the interaction-based inductive bias can guide the model to learn atomic interactions that are consistent with physical reality. As a case study to demonstrate practical usefulness, our method is tested for predicting the efficacy of Nirmatrelvir against SARS-CoV-2 variants. EHIGN successfully recognizes the changes in the efficacy of Nirmatrelvir for different SARS-CoV-2 variants with meaningful reasons.

Finding candidate molecules with favorable pharmacological activity, low toxicity, and proper pharmacokinetic properties is an important task in drug discovery. Deep neural networks have made impressive progress in accelerating and improving drug discovery. However, these techniques rely on a large amount of label data to form accurate predictions of molecular properties. At each stage of the drug discovery pipeline, usually, only a few biological data of candidate molecules and derivatives are available, indicating that the application of deep neural networks for low-data drug discovery is still a formidable challenge. Here, we propose a meta learning architecture with graph attention network, Meta-GAT, to predict molecular properties in low-data drug discovery. The GAT captures the local effects of atomic groups at the atom level through the triple attentional mechanism and implicitly captures the interactions between different atomic groups at the molecular level. GAT is used to perceive molecular chemical environment and connectivity, thereby effectively reducing sample complexity. Meta-GAT further develops a meta learning strategy based on bilevel optimization, which transfers meta knowledge from other attribute prediction tasks to low-data target tasks. In summary, our work demonstrates how meta learning can reduce the amount of data required to make meaningful predictions of molecules in low-data scenarios. Meta learning is likely to become the new learning paradigm in low-data drug discovery. The source code is publicly available at: https://github.com/lol88/Meta-GAT.

Drug-drug interactions (DDIs) trigger unexpected pharmacological effects in vivo, often with unknown causal mechanisms. Deep learning methods have been developed to better understand DDI. However, learning domain-invariant representations for DDI remains a challenge. Generalizable DDI predictions are closer to reality than source domain predictions. For existing methods, it is difficult to achieve out-of-distribution (OOD) predictions. In this article, focusing on substructure interaction, we propose DSIL-DDI, a pluggable substructure interaction module that can learn domain-invariant representations of DDIs from source domain. We evaluate DSIL-DDI on three scenarios: the transductive setting (all drugs in test set appear in training set), the inductive setting (test set contains new drugs that were not present in training set), and OOD generalization setting (training set and test set belong to two different datasets). The results demonstrate that DSIL-DDI improve the generalization and interpretability of DDI prediction modeling and provides valuable insights for OOD DDI predictions. DSIL-DDI can help doctors ensuring the safety of drug administration and reducing the harm caused by drug abuse.

With the rapid development of proteomics and the rapid increase of target molecules for drug action, computer-aided drug design (CADD) has become a basic task in drug discovery. One of the key challenges in CADD is molecular representation. High-quality molecular expression with chemical intuition helps to promote many boundary problems of drug discovery. At present, molecular representation still faces several urgent problems, such as the polysemy of substructures and unsmooth information flow between atomic groups. In this research, we propose a deep contextualized Bi-LSTM architecture, Mol2Context-vec, which can integrate different levels of internal states to bring dynamic representations of molecular substructures. And the obtained molecular context representation can capture the interactions between any atomic groups, especially a pair of atomic groups that are topologically distant. Experiments show that Mol2Context-vec achieves state-of-the-art performance on multiple benchmark datasets. In addition, the visual interpretation of Mol2Context-vec is very close to the structural properties of chemical molecules as understood by humans. These advantages indicate that Mol2Context-vec can be used as a reliable and effective tool for molecular expression. Availability: The source code is available for download in https://github.com/lol88/Mol2Context-vec.