HBGSA: Hydrogen Bond Graph with Self-Attention for Drug-Target Binding Affinity Prediction

Quantitative estimation of protein-ligand binding affinity from three-dimensional complex structures is a fundamental task in structure-based computational chemistry and molecular modeling. Reliable prediction remains challenging because available structure-affinity data are limited, experimentally heterogeneous, conformation-dependent, and sensitive to dataset partitioning. RAVEN (Randomized Atomistic Views with Ensemble Neural Reservoirs) utilizes a multihead reservoir of independently initialized and fully frozen atomistic graph encoders to generate diverse structural projections without end-to-end optimization of the graph representation. These projections are integrated with a deterministic physicochemical interaction fingerprint and processed by heterogeneous supervised readers, including neural and tree-based regressors, whose outputs are combined through validation-based nonnegative fusion. The random reservoir expands structural feature coverage across independent encoder realizations, whereas the explicit physicochemical descriptors and heterogeneous readers contribute complementary information and distinct inductive biases. Evaluation on a similarity-isolated PDBbind 2020R1 split reconstructed using GEMS similarity resources, together with the protected CASF-2016 subset, demonstrated strong predictive performance. The results indicate that frozen multi-view graph representations, explicit physicochemical statistics, and heterogeneous model fusion provide a robust and flexible framework for protein-ligand binding-affinity prediction.

Explainable artificial intelligence approaches accelerate drug discovery by improving molecular representation learning, identifying key molecular structures, and rationalizing drug property prediction. However, developing end-to-end explainable models for target-specific structure-activity relationship modeling remains challenging because compound-protein interaction data are often limited for individual targets, and small changes in chemical substituents or local structural motifs can cause large differences in molecular properties. Therefore, effectively leveraging structural and property information to identify key moieties associated with compound-protein affinity is essential. We propose a graph neural network (GNN) framework that uses property and structural information from activity-cliff molecule pairs targeting specific proteins to predict compound-protein affinity, measured by half-maximal inhibitory concentration (IC50), and explain property differences. To improve explainability, we trained GNNs with structure-aware loss functions using group lasso and sparse group lasso regularization, which prune and highlight molecular subgraphs relevant to activity differences. We applied this framework to activity-cliff data from molecules targeting six tyrosine-protein kinases across the Src, Abl, and Tec families, as well as anaplastic lymphoma kinase. Integrating common- and uncommon-node information with sparse group lasso improved target-specific molecular property prediction, producing lower root mean square errors and higher Pearson correlation coefficients. Regularization also enhanced GNN feature attribution by improving graph-level global direction scores and atom-level coloring accuracy. These results support more interpretable drug discovery pipelines, particularly for identifying critical molecular substructures during lead optimization.

DuaDeep-SeqAffinity is a sequence-only deep learning framework that predicts antibody--antigen binding affinity directly from primary amino acid sequences, avoiding the cost and scarcity of resolved three-dimensional structures. The antigen and the antibody heavy and light chains are processed as three independent streams, each embedded with a frozen ESM-2 protein language model and passed through parallel Transformer and convolutional neural network (CNN) branches before late fusion, a decoupled design intended to preserve local complementarity-determining region (CDR) signal that monolithic encoders can dilute. On a sequence-disjoint split of the AbRank benchmark, the model achieves a Pearson correlation of 0.683, an R^2 of 0.460, and a pairwise ranking AUC of 0.895, significantly outperforming single-branch ablations (paired t-test, p < 0.05). Attention-map and gradient-based saliency analyses further show that the model preferentially attends to CDR loops and candidate epitope residues, supporting its use as a scalable, structure-free tool for high-throughput antibody screening.