By integrating AlphaFold3-derived single, pair, and structure-based embeddings through adaptive fusion, AlphaDTA improves generalization on structurally nonredundant benchmarks and demonstrates utility for target-specific drug repurposing.
Abstract
Accurate prediction of drug-target binding affinity plays an important role in structure-based drug discovery, yet existing approaches are constrained by their reliance on scarce experimentally determined protein-ligand complex structures. In this context, recent advances in biomolecular structure prediction models, such as AlphaFold3, have emerged as a promising approach to alleviate the scarcity of experimentally determined protein-ligand complex structures. In this study, we introduce AlphaDTA, a framework that integrates AlphaFold3-predicted structures and embeddings for drug-target binding affinity prediction. AlphaDTA processes two types of AlphaFold3 embeddings, single and pair embeddings. We utilized the single embeddings at both fine-grained and coarse-grained levels to capture local interaction patterns and global binding context, and used the pair embeddings to encode cross-molecular relational features. The AlphaFold3-predicted structures are further processed by a three-dimensional structure-based geometric encoder to produce corresponding structural embedding representations. The resulting single, pair, and structural embeddings are then integrated through adaptive fusion for affinity prediction. When we evaluated AlphaDTA using recently proposed PDBbind data splits designed to reduce train-test structural overlap, AlphaDTA achieved state-of-the-art or competitive performance across multiple independent benchmarks. In a case study on the cystic fibrosis transmembrane conductance regulator, AlphaDTA correctly identifies a clinically approved potentiator and suggests a potential repurposing candidate among FDA-approved drugs.Scientific contribution AlphaDTA enables accurate drug-target binding affinity prediction without relying on experimentally determined protein-ligand complex structures. By integrating AlphaFold3-derived single, pair, and structure-based embeddings through adaptive fusion, AlphaDTA improves generalization on structurally nonredundant benchmarks and demonstrates utility for target-specific drug repurposing.
Accurate prediction of drug-target binding affinity (DTA) is a key task in virtual screening. However, current computational methods face a key challenge: sequence-based approaches often fail to capture critical spatial information, while structure-based models rely on computationally expensive 3D coordinates, which restrict their scalability. To address this issue, we propose StructuraDTA, a novel multimodal framework that adopts an implicit structure modeling strategy. Instead of using static protein folding data, our method encodes drug molecular graphs via Graph Isomorphism Networks (GINs) to capture fine-grained topological features. Meanwhile, we optimize protein representations by integrating probabilistic structural priors into a pretrained language model, which effectively simulates thermodynamic conformational flexibility without relying on explicit 3D structural data. A bidirectional cross-attention mechanism is then used to dynamically align these heterogeneous feature modalities. Comprehensive evaluations on the Davis and KIBA benchmark datasets show that StructuraDTA stably outperforms state of-the-art comparison methods. Importantly, the model exhibits strong robustness in cold-start scenarios, and can accurately predict binding affinities for previously unseen drugs and targets. By retaining the predictive performance of structure based models while maintaining the high inference efficiency of sequence-based methods, we provide an accurate and scalable solution to accelerate genome-scale drug discovery research.
Junlin Xu, Ye Yuan, Menglong Hu et al.· IEEE journal of biomedical a...· 0 citations
Accurate identification of near-native ligand binding poses is a central challenge in structure-based drug design. From a physical point of view, the successful construction of a protein–ligand complex structure is dependent on whether protein and ligand can form enough atomically pairwise interactions that result in a global energy minimum. In this work, we report a machine learning scoring strategy for protein–ligand screening which explicitly considers the Native Contact Ratio (NCR), a topology inspired metric that quantifies the preservation of protein–ligand interfacial contacts as well as interaction energy. This physics-awared supervision strategy provides a simple but efficient gradient field that faithfully reflects the complicated protein energy landscape than conventional 3D coordinate-based objectives. Building on this principle, we present DeepNCR, an energy-informed Transformer framework that encodes approximate Coulombic and dispersive interaction potentials across the protein–ligand binding interface. Furthermore, we introduce a feature pruning step that compresses the interaction tensor from 1470 to 868 dimensions, further improving signal-to-noise ratio and directing model attention toward the interaction motifs critical for binding specificity. The model optimizes topological objectives and at inference drives pose refinement through a differentiable hybrid gradient field integrating predicted NCR and AutoDock Vina energetics. Extensive evaluation on the CASF-2016 benchmark and the 3D-DISCO cross-docking data set demonstrates consistently high performance: a Top-1 docking success rate of 94.7%, a 1% Enrichment Factor of 21.21 in virtual screening, and a Top-1 cross-docking success rate of 34.8%. Mechanistic analysis reveals that NCR-guided optimization enables decoy escaping from local energy minima and drives the recovery of disrupted native interactions, confirming that NCR captures the physical determinants of binding rather than mere geometric proximity.
Zhenqiang Zhang, Zhihao Wang, Yang Liu et al.· Journal of Chemical Informat...· 0 citations
Abstract Motivation To enable real-world protein-ligand affinity prediction, not only out-of-distribution generalization but also robustness to variable structural availability and quality should be considered in model design. Results We present AlignNet, a hierarchical representation alignment framework that mitigates intra- and inter-molecular heterogeneity to learn robust protein-ligand embeddings for generalizable affinity prediction, even from sequence-level inputs. Its intra-molecular module projects unimodal and multimodal features into a unified space, aligning augmented multimodal views for feature fusion and unimodal with multimodal embeddings to distill multimodal priors for structure-agnostic inference. Its inter-molecular module aligns protein and ligand embeddings for cross-molecular integration. Extensive experiments show that AlignNet (i) achieves highly competitive performance, with up to a 20.4% gain in SCC on the challenging LBA 30% split under sequence-only settings, suggesting improved out-of-distribution generalization; and (ii) learns well-separated affinity-related clusters, supporting reliable structure-independent prediction. Availability and implementation AlignNet is available at https://github.com/altriavin/AlignNet.
Xiaowen Hu, Hongyi Huang, Hao Sun et al.· Bioinformatics· 0 citations
MultiGeo is a DTA prediction framework that explicitly leverages multiple protein conformations rather than a single snapshot, and introduces a disagreement-aware gating mechanism that adaptively fuses this ensemble representation with the dominant structure only when the additional conformers provide complementary information.
Ruida Zeng, Cheng Guo, Yajie Meng et al.· 0 citations
Abstract Motivation Binding affinity governs how proteins interact and underlies essential biological processes. Computational approaches have been developed to simulate and predict protein binding, but the scarcity of high-quality data has imposed significant constraints. One consequence is that most methods focus on predicting mutational changes in binding affinity (ΔΔG), rather than binding affinity (ΔG) itself. This practice risks overfitting to skewed data distributions, limiting the generalizability of predictions. Recent advances in protein structure prediction have enabled computational modeling of protein conformations in mass, providing rich structural information from which binding interactions can be largely explained. However, leveraging these advances for effective prediction of binding affinity has yet to translate into reliable predictions. Results We present PreFold-dG, a model that estimates binding affinities of protein complexes utilizing intermediate embeddings from Boltz-2, an open-source foundation model for protein structure prediction. Our approach aggregates residue-level information weighted by interresidue distance, and predicts ΔG directly rather than its derivative, ΔΔG. PreFold-dG achieved state-of-the-art performance on well-established binding affinity prediction benchmarks and demonstrated robustness on independent test sets. Ablation studies suggest that all intermediate embeddings are utilized in the prediction, whereas their contributions to modeling ΔΔG and ΔG vary. We further validated our model through case studies on real-world broadly neutralizing antibody data with evolutionary relevance. Availability https://github.com/LGAI-Research/PreFold-dG.
Sungjoon Park, Soorin Yim, Dongyun Kim et al.· Bioinformatics· 0 citations
By combining protein language model embeddings with topology-adaptive geometric reasoning, DiConSite offers a reusable framework for residue-level protein interaction analysis and achieves consistently strong and often best-performing results, while improving robustness to structural uncertainty and cross-modal variation.
Shou-Zhi Chen, Zhenchao Tang, Linlin You et al.· IEEE Transactions on Pattern...· 1 citation