StructureNet: Physics-Informed Hybridized Deep Learning Framework for Protein-Ligand Binding Affinity Prediction.

Predicting protein-ligand binding affinity is a central issue in drug design. Various deep learning models have been published in recent years, where many of them rely on 3D protein-ligand complex structures as input and tend to focus on the single task of reproducing binding affinity. In this study, we have developed a graph neural network model called PLANET (Protein-Ligand Affinity prediction NETwork). This model takes the graph-represented 3D structure of the binding pocket on the target protein and the 2D chemical structure of the ligand molecule as input. It was trained through a multi-objective process with three related tasks, including deriving the protein-ligand binding affinity, protein-ligand contact map, and ligand distance matrix. Besides the protein-ligand complexes with known binding affinity data retrieved from the PDBbind database, a large number of non-binder decoys were also added to the training data for deriving the final model of PLANET. When tested on the CASF-2016 benchmark, PLANET exhibited a scoring power comparable to the best result yielded by other deep learning models as well as a reasonable ranking power and docking power. In virtual screening trials conducted on the DUD-E benchmark, PLANET's performance was notably better than several deep learning and machine learning models. As on the LIT-PCBA benchmark, PLANET achieved comparable accuracy as the conventional docking program Glide, but it only spent less than 1% of Glide's computation time to finish the same job because PLANET did not need exhaustive conformational sampling. Considering the decent accuracy and efficiency of PLANET in binding affinity prediction, it may become a useful tool for conducting large-scale virtual screening.

Predicting protein-ligand binding affinity is a crucial and challenging task in structure-based drug discovery. With the accumulation of complex structures and binding affinity data, various machine-learning scoring functions, particularly those based on deep learning, have been developed for this task, exhibiting superiority over their traditional counterparts. A fusion model sequentially connecting a graph neural network (GNN) and a convolutional neural network (CNN) to predict protein-ligand binding affinity is proposed in this work. In this model, the intermediate outputs of the GNN layers, as supplementary descriptors of atomic chemical environments at different levels, are concatenated with the input features of CNN. The model demonstrates a noticeable improvement in performance on CASF-2016 benchmark compared to its constituent CNN models. The generalization ability of the model is evaluated by setting a series of thresholds for ligand extended-connectivity fingerprint similarity or protein sequence similarity between the training and test sets. Masking experiment reveals that model can capture key interaction regions. Furthermore, the fusion model is applied to a virtual screening task for a novel target, PI5P4Kα. The fusion strategy significantly improves the ability of the constituent CNN model to identify active compounds. This work offers a novel approach to enhancing the accuracy of deep learning models in predicting binding affinity through fusion strategies.

Accurate prediction of protein-ligand binding affinity is pivotal for drug design and discovery. Here, we proposed a novel deep fusion graph neural networks framework named FGNN to learn the protein-ligand interactions from the 3D structures of protein-ligand complexes. Unlike 1D sequences for proteins or 2D graphs for ligands, the 3D graph of protein-ligand complex enables the more accurate representations of the protein-ligand interactions. Benchmark studies have shown that our fusion models FGNN can achieve more accurate prediction of binding affinity than any individual algorithm. The advantages of fusion strategies have been demonstrated in terms of expressive power of data, learning efficiency and model interpretability. Our fusion models show satisfactory performances on diverse data sets, demonstrating their generalization ability. Given the good performances in both binding affinity prediction and virtual screening, our fusion models are expected to be practically applied for drug screening and design. Our work highlights the potential of the fusion graph neural network algorithm in solving complex prediction problems in computational biology and chemistry. The fusion graph neural networks (FGNN) model is freely available in https://github.com/LinaDongXMU/FGNN.

Deep learning has led to major advances in fields like natural language processing, computer vision, and other Euclidean data domains. Yet, many important fields have data defined on irregular domains, requiring graphs to be explicitly modeled. One such application is drug discovery. Recently, research has found that using graph neural network (GNN) models, given enough data, can perform better than using human-engineered fingerprints or descriptors in predicting molecular properties of potential antibiotics.We explore these state-of-the-art AI models on predicting desirable molecular properties for drugs that can inhibit SARS-CoV-2. We build upon the GNN models with ideas from recent breakthroughs in geometric deep learning, inspired by the topologies of the molecules. In this poster paper, we present an overview of the drug discovery framework, drug-target interaction framework, and GNNs. Preliminary results on two COVID-19 related datasets are encouraging, achieving a ROC-AUC of 0.72 for FDA-approved chemical library screened against SARS-CoV-2 in vitro.

Past events have revealed that widespread blackouts are mostly a result of cascading failures in the power grid. Understanding the underlining mechanisms of cascading failures can help in developing strategies to minimize the risk of such events. Moreover, a real-time detection of precursors to cascading failures will help operators take measures to prevent their propagation. Currently, the well-established probabilistic and physics-based models of cascading failures offer low computational efficiency, hindering them to be used only as offline tools. In this work, we develop a data-driven methodology for online estimation of the risk of cascading failures. We utilize a physics-based cascading failure model to generate a cascading failure dataset considering different operating conditions and failure scenarios, thus obtaining a sample space covering a large set of power grid states that are labeled as safe or unsafe. We use the synthetic data to train deep learning architectures, namely Feed-forward Neural Networks (FNN) and Graph Neural Networks (GNN). With the development of GNNs, improved performance is achieved with graph-structured data, and GNNs can generalize to graphs of diverse sizes. A comparison between FNN and GNN is made and the GNNs inductive capability is demonstrated via test grids. Furthermore, we apply transfer learning to improve the performance of a pre-trained GNN model on power grids not seen in the training process. The GNN model shows accuracy and balanced accuracy above 96% on selected test datasets not used in the training. Conversely, the FNN shows accuracy above 85% and balanced accuracy above 81% on test datasets unseen during training. Overall, the GNN model is successful in determining, if one or several simultaneous outages result in a critical grid state, under specific grid operating conditions.

In the drug discovery process and repurposing of existing drugs, accurately identifying ligands with high binding affinity to proteins is a very critical step. However, it sinks a lot of time and resources to detect the protein-ligand binding affinity through biological experiments. Therefore, it is very necessary to develop an accurate and reliable computational method to predict the binding affinity between protein and ligand. At present, some computational methods have been proposed to predict the protein-ligand binding affinity, but the absence of protein-ligand complexes structures restricts some predictive methods that require input the complexes structures. In this paper, a novel deep-learning-based method is proposed, named DPLA, to predict binding affinity by integrating multilevel information of protein and ligand. More specifically, our model extracted some important information, such as sequence representation, structural property representation of amino acids in protein and protein binding pocket, MACCS key ligand molecular fingerprint and ligand molecular network features. This method was tested on the PDBbind core set, and we compared it with some recent state-of-art protein-ligand affinity prediction methods. The excellent performance shows that DPLA is an accurate and reliable method for affinity prediction.

Generalized predictive analysis of reactions in paper devices via graph neural networks

Protein-ligand interactions are the molecular basis of many important cellular activities, such as gene regulation, cell metabolism, and signal transduction. Protein-ligand binding affinity is a crucial metric of the strength of the interaction between the two, and accurate prediction of its binding affinity is essential for discovering drugs' new uses. So far, although many predictive models based on machine learning and deep learning have been reported, most of the models mainly focus on one-dimensional sequence and two-dimensional structural characteristics of proteins and ligands, but fail to deeply explore the detailed interaction information between proteins and ligand atoms in the binding pocket region of three-dimensional space. In this study, we introduced a novel 4D tensor feature to capture key interactions within the binding pocket and developed a three-dimensional convolutional neural network (CNN) model based on this feature. Using ten-fold cross-validation, we identified the optimal parameter combination and pocket size. Additionally, we employed feature engineering to extract features across multiple dimensions, including one-dimensional sequences, two-dimensional structures of the ligand and protein, and three-dimensional interaction features between them. We proposed an efficient protein-ligand binding affinity prediction model MCDTA (multi-dimensional convolutional drug-target affinity), built on a multi-dimensional convolutional neural network framework. Feature ablation experiments revealed that the 4D tensor feature had the most significant impact on model performance. MCDTA performed exceptionally well on the PDBbind v.2020 dataset, achieving an RMSE of 1.231 and a PCC of 0.823. In comparative experiments, it outperformed five other mainstream binding affinity prediction models, with an RMSE of 1.349 and a PCC of 0.795. Moreover, MCDTA demonstrated strong generalization ability and practical screening performance across multiple benchmark datasets, highlighting its reliability and accuracy in predicting protein-ligand binding affinity. The code for MCDTA is available at https://github.com/dfhuang-AI/MCDTA .

Accurate prediction of protein-ligand bound poses and their affinities is essential in structure-based drug discovery. Here, we present an integrated deep-learning framework that disentangles the two core tasks─affinity estimation and pose evaluation─within complementary graph neural network architectures. BA-Pred is for predicting binding affinity and RMSD-Pred is for binding pose assessment, predicting the root-mean-squared deviation of ligand poses from crystal structures. Both models employ a Gated Graph Convolutional Network with Learnable Structural Positional Encoding (GatedGCN-LSPE) architecture to capture spatial and chemical dependencies across protein-ligand graphs. BA-Pred achieved state-of-the-art scoring power on the CASF-2016 benchmark with a root-mean-squared error of 1.10 pKd, while RMSD-Pred exhibited strong docking power with a top-1 success rate of 96%, comparable to the best reported deep-learning scoring functions. The robust generalization capability of RMSD-Pred was further validated on the external Astex diverse set and PoseBusters benchmarks, where it significantly improved the pose selection success rates of AutoDock-GPU by up to 33.1%. The accuracy of our methodology was demonstrated on pharmaceutical targets in the 16th Critical Assessment of Structure Prediction, where our approach ranked second in the ligand binding affinity prediction category. By using our models, an integrated pipeline was developed for virtual screening, where pose selection was performed with RMSD-Pred and binding affinities were predicted with BA-Pred. This combined approach demonstrated robust screening performance, achieving an enrichment factor (EF) 1% of 21.1 on the CASF-2016 benchmark. Furthermore, on the LIT-PCBA benchmark, rescoring poses docked by AutoDock-GPU with our pipeline significantly improved the EF 1% from 2.18 to 3.19. These various benchmark results demonstrate that our graph-neural network models show good and balanced performance in diverse protein-ligand interaction prediction tasks. Thus, we expect that our models will serve as a promising framework to accelerate the drug discovery process.

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.

Developing fast and accurate computational models to simulate intricate physical phenomena has been a persistent research challenge. Recent studies have demonstrated remarkable capabilities in predicting various physical outcomes through machine learning-assisted approaches. However, it remains challenging to generalize current methods, usually crafted for a specific problem, to other more complex or broader scenarios. To address this challenge, we developed graph neural network (GNN) models with enhanced generalizability derived from the distinct GNN architecture and neural operator techniques. As a proof of concept, we employ our GNN models to predict finite element (FE) simulation results for three-dimensional solid mechanics problems with varying boundary conditions. Results show that our GNN model achieves accurate and robust performance in predicting the stress and deformation profiles of structures compared with FE simulations. Furthermore, the neural operator embedded GNN approach enables learning and predicting various solid mechanics problems in a generalizable fashion, making it a promising approach for surrogate modeling.

Sex classification is a major benchmark of previous work in learning on the structural connectome, a naturally occurring brain graph that has proven useful for studying cognitive function and impairment. While graph neural networks (GNNs), specifically graph convolutional networks (GCNs), have gained popularity lately for their effectiveness in learning on graph data, achieving strong performance in adult sex classification tasks, their application to pediatric populations remains unexplored. We seek to characterize the capacity for GNN models to learn connectomic patterns on pediatric data through an exploration of training techniques and architectural design choices. Two datasets comprising an adult BRIGHT dataset (N = 147 Hodgkin's lymphoma survivors and N = 162 age similar controls) and a pediatric Human Connectome Project in Development (HCP-D) dataset (N = 135 healthy subjects) were utilized. Two GNN models (GCN simple and GCN residual), a deep neural network (multi-layer perceptron), and two standard machine learning models (random forest and support vector machine) were trained. Architecture exploration experiments were conducted to evaluate the impact of network depth, pooling techniques, and skip connections on the ability of GNN models to capture connectomic patterns. Models were assessed across a range of metrics including accuracy, AUC score, and adversarial robustness. GNNs outperformed other models across both populations. Notably, adult GNN models achieved 85.1% accuracy in sex classification on unseen adult participants, consistent with prior studies. The extension of the adult models to the pediatric dataset and training on the smaller pediatric dataset were sub-optimal in their performance. Using adult data to augment pediatric models, the best GNN achieved comparable accuracy across unseen pediatric (83.0%) and adult (81.3%) participants. Adversarial sensitivity experiments showed that the simple GCN remained the most robust to perturbations, followed by the multi-layer perceptron and the residual GCN. These findings underscore the potential of GNNs in advancing our understanding of sex-specific neurological development and disorders and highlight the importance of data augmentation in overcoming challenges associated with small pediatric datasets. Further, they highlight relevant tradeoffs in the design landscape of connectomic GNNs. For example, while the simpler GNN model tested exhibits marginally worse accuracy and AUC scores in comparison to the more complex residual GNN, it demonstrates a higher degree of adversarial robustness.

In drug discovery, determining the binding affinity and functional effects of small-molecule ligands on proteins is critical. Current computational methods can predict these protein–ligand interaction properties but often lose accuracy without high-resolution protein structures and falter in predicting functional effects. Here we introduce PSICHIC (PhySIcoCHemICal graph neural network), a framework incorporating physicochemical constraints to decode interaction fingerprints directly from sequence data alone. This enables PSICHIC to attain capabilities in decoding mechanisms underlying protein–ligand interactions, achieving state-of-the-art accuracy and interpretability. Trained on identical protein–ligand pairs without structural data, PSICHIC matched and even surpassed leading structure-based methods in binding-affinity prediction. In an experimental library screening for adenosine A1 receptor agonists, PSICHIC discerned functional effects effectively, ranking the sole novel agonist within the top three. PSICHIC’s interpretable fingerprints identified protein residues and ligand atoms involved in interactions, and helped in unveiling selectivity determinants of protein–ligand interaction. We foresee PSICHIC reshaping virtual screening and deepening our understanding of protein–ligand interactions. Predicting the binding affinity between small-molecule ligands and proteins is a key task in drug discovery; however, sequence-based methods are often less accurate than structure-based ones. Koh et al. develop a graph neural network using physicochemical constraints that discovers interactions between small molecules and proteins directly from sequence data and that can achieve state-of-the-art performance without the need for costly, experimental 3D structures.

Geometric graph learning with extended atom-types features for protein-ligand binding affinity prediction

Drug response prediction is an essential part of precision medicine, which assesses the efficacy of drugs in specific cancer cell lines. Recently, numerous deep learning models have been developed for drug response prediction. The ability to effectively represent complicated interactions within a network makes Graph Neural Network (GNN) models a prominent area of exploration. To exploit the diverse capabilities of different GNN models, the proposed model uses an ensemble approach that combines results from Graph Convolutional Network (GCN), Graph SAmple and aggreGatE Network (GraphSAGE) and Graph Attention Network (GAT)-based models for drug response prediction. The proposed ensemble GNN model is used to predict the efficacy of drugs in treating leukemia. The model outperformed individual models when evaluated with the GDSC1000 dataset, with lower root mean squared error, higher Pearson’s correlation coefficient, higher coefficient of determination and higher Spearman’s correlation coefficient. Furthermore, most of the drugs identified by the model as potential candidates for the treatment of leukemia are currently in clinical trials or have supporting evidence in the PubMed literature database.