DTA-GTOmega:利用 OmegaFold 蛋白结构的图形变换器增强药物与目标的结合亲和力预测。

IF 4.7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Lijun Quan, Jian Wu, Yelu Jiang, Deng Pan, Lyu Qiang
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引用次数: 0

摘要

了解药物与蛋白质之间的相互作用对于阐明药物机制和优化药物开发至关重要。然而,现有方法在表示靶标的三维结构和捕捉药物与靶标之间的复杂关系方面存在局限性。本研究提出了一种预测药物与靶点结合亲和力的新方法--DTA-GTOmega。DTA-GTOmega 利用 OmegaFold 预测蛋白质三维结构并构建靶标图,同时利用 RDKit 处理药物 SMILES 序列以生成药物图。通过采用多层图转换模块和共关注模块,该方法有效地整合了药物的原子级特征和靶标的残基级特征,准确地模拟了药物和靶标之间复杂的相互作用,从而显著提高了结合亲和力预测的准确性。在冷启动设置下,我们的方法在 KIBA、Davis 和 BindingDB_Kd 等基准数据集上的表现优于现有技术。此外,DTA-GTOmega 在涉及 DrugBank 数据以及与心血管和神经系统相关疾病有关的药物-靶点相互作用的真实世界 DTI 场景中表现出了极具竞争力的性能,突显了其强大的泛化能力。此外,引入的 DTI 评估指标进一步验证了 DTA-GTOmega 在处理不平衡数据方面的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
DTA-GTOmega: Enhancing Drug-Target Binding Affinity Prediction with Graph Transformers Using OmegaFold Protein Structures.

Understanding drug-protein interactions is crucial for elucidating drug mechanisms and optimizing drug development. However, existing methods have limitations in representing the three-dimensional structure of targets and capturing the complex relationships between drugs and targets. This study proposes a new method, DTA-GTOmega, for predicting drug-target binding affinity. DTA-GTOmega utilizes OmegaFold to predict protein three-dimensional structure and construct target graphs, while processing drug SMILES sequences with RDKit to generate drug graphs. By employing multi-layer graph transformer modules and co-attention modules, this method effectively integrates atomic-level features of drugs and residue-level features of targets, accurately modeling the complex interactions between drugs and targets, thereby significantly improving the accuracy of binding affinity predictions. Our method outperforms existing techniques on benchmark datasets such as KIBA, Davis, and BindingDB_Kd under cold-start setting. Moreover, DTA-GTOmega demonstrates competitive performance in real-world DTI scenarios involving DrugBank data and drug-target interactions related to cardiovascular and nervous system-related diseases, highlighting its robust generalization capabilities. Additionally, the introduced DTI evaluation metrics further validate DTA-GTOmega's potential in handling imbalanced data.

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来源期刊
Journal of Molecular Biology
Journal of Molecular Biology 生物-生化与分子生物学
CiteScore
11.30
自引率
1.80%
发文量
412
审稿时长
28 days
期刊介绍: Journal of Molecular Biology (JMB) provides high quality, comprehensive and broad coverage in all areas of molecular biology. The journal publishes original scientific research papers that provide mechanistic and functional insights and report a significant advance to the field. The journal encourages the submission of multidisciplinary studies that use complementary experimental and computational approaches to address challenging biological questions. Research areas include but are not limited to: Biomolecular interactions, signaling networks, systems biology; Cell cycle, cell growth, cell differentiation; Cell death, autophagy; Cell signaling and regulation; Chemical biology; Computational biology, in combination with experimental studies; DNA replication, repair, and recombination; Development, regenerative biology, mechanistic and functional studies of stem cells; Epigenetics, chromatin structure and function; Gene expression; Membrane processes, cell surface proteins and cell-cell interactions; Methodological advances, both experimental and theoretical, including databases; Microbiology, virology, and interactions with the host or environment; Microbiota mechanistic and functional studies; Nuclear organization; Post-translational modifications, proteomics; Processing and function of biologically important macromolecules and complexes; Molecular basis of disease; RNA processing, structure and functions of non-coding RNAs, transcription; Sorting, spatiotemporal organization, trafficking; Structural biology; Synthetic biology; Translation, protein folding, chaperones, protein degradation and quality control.
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