In silico prediction of drug-target interactions (DTI) is significant for drug discovery because it can largely reduce timelines and costs in the drug development process. Specifically, deep learning-based DTI approaches have been shown promising results in terms of accuracy and low cost for the prediction. However, they pay little attention to the interpretability of their prediction results and feature-level interactions between a drug and a target. In this study, we propose a novel interpretable framework that can provide reasonable cues for the interaction sites. To this end, we elaborately design a gated cross-attention mechanism that crossly attends drug and target features by constructing explicit interactions between these features. The gating function in the method enables neural models to focus on salient regions over entire sequences of drugs and proteins, and the byproduct from the function, which is the attention map, could serve as interpretable factors. The experimental results show the efficacy of the proposed method in two DTI datasets. Additionally, we show that gated cross-attention can sensitively react to the mutation, and this result could provide insights into the identification of novel drugs targeting mutant proteins.
BVSIMC: Bayesian Variable Selection-Guided Inductive Matrix Completion for Improved and Interpretable Drug Discovery
Department of Statistics University of South Carolina（统计学系南卡罗来纳大学）；Department of Biostatistics University of South Carolina（生物统计学系南卡罗来纳大学）；Department of Biostatistics University of Florida（生物统计学系佛罗里达大学）；Department of Surgery University of Florida（外科医学系佛罗里达大学）；Department of Statistics George Mason University（统计学系乔治·梅森大学）
DrugReasoner: Interpretable Drug Approval Prediction with a Reasoning-augmented Language Model
Regenerative Medicine Research Center, Isfahan University of Medical Sciences（再生医学研究中心，伊斯法罕医科大学）；Isfahan University of Medical Sciences（伊斯法罕医科大学）；Isfahan Neuroscience Research Center, Isfahan University of Medical Sciences（伊斯法罕神经科学研究中心，伊斯法罕医科大学）；Department of Electrical and Computer Engineering, Isfahan University of Technology（电气与计算机工程系，伊斯法罕技术大学）
Technical University of Munich（慕尼黑工业大学）；University of Alberta（阿尔伯塔大学）
Drug-mediated blockade of the voltage-gated potassium channel(hERG) and the voltage-gated sodium channel (Nav1.5) can lead to severe cardiovascular complications. This rising concern has been reflected in the drug development arena, as the frequent emergence of cardiotoxicity from many approved drugs led to either discontinuing their use or, in some cases, their withdrawal from the market. Predicting potential hERG and Nav1.5 blockers at the outset of the drug discovery process can resolve this problem and can, therefore, decrease the time and expensive cost of developing safe drugs. One fast …
LIT AI Lab & Institute for Machine Learning, Johannes Kepler University Linz（林茨约翰开普勒大学LIT人工智能实验室和机器学习研究所）；Computational Chemistry & Biology, Merck KGaA（默克集团计算化学与生物学部）
Without any means of interpretation, neural networks that predict molecular properties and bioactivities are merely black boxes. We will unravel these black boxes and will demonstrate approaches to understand the learned representations which are hidden inside these models. We show how single neurons can be interpreted as classifiers which determine the presence or absence of pharmacophore- or toxicophore-like structures, thereby generating new insights and relevant knowledge for chemistry, pharmacology and biochemistry. We further discuss how these novel pharmacophores/toxicophores can be det…
Drug discovery aims to find novel compounds with specified chemical property profiles. In terms of generative modeling, the goal is to learn to sample molecules in the intersection of multiple property constraints. This task becomes increasingly challenging when there are many property constraints. We propose to offset this complexity by composing molecules from a vocabulary of substructures that we call molecular rationales. These rationales are identified from molecules as substructures that are likely responsible for each property of interest. We then learn to expand rationales into a full …
A systematic investigation of molecular encoding methods for drug property predictions across neural network and Transformer encoder-based model
School of Medicine, National Tsing Hua University（国立清华大学医学院）；Institute of Bioinformatics and Structural Biology, National Tsing Hua University（国立清华大学生物信息学与结构生物学研究所）；Department of Life Science, National Tsing Hua University（国立清华大学生命科学系）；Interdisciplinary Program of Life Sciences and Medicine, National Tsing Hua University（国立清华大学生命科学与医学跨学科计划）
DrugReason: Dynamic Multi-View Reasoning over Knowledge Graph and Language Evidence for Drug Repurposing
University of North Carolina at Chapel Hill（北卡罗来纳大学教堂山分校）；Stevens Institute of Technology（史蒂文斯理工学院）；Emory University（埃默里大学）；Massachusetts Institute of Technology（麻省理工学院）
Coder as Editor: Code-driven Interpretable Molecular Editing
Institute for AI Industry Research, Tsinghua University（人工智能产业研究院，清华大学）；Department of Computer Science and Technology, Tsinghua University（计算机科学与技术系，清华大学）；School of Pharmaceutical Sciences, Peking University（北京大学药学院）；University of Electronic Science and Technology of China（电子科技大学）
Tsinghua University（清华大学）；Ping An Technology（平安科技）；Beijing University of Chemical Technology（北京化工大学）；Lanzhou University（兰州大学）
How to produce expressive molecular representations is a fundamental challenge in AI-driven drug discovery. Graph neural network (GNN) has emerged as a powerful technique for modeling molecular data. However, previous supervised approaches usually suffer from the scarcity of labeled data and have poor generalization capability. Here, we proposed a novel Molecular Pre-training Graph-based deep learning framework, named MPG, that leans molecular representations from large-scale unlabeled molecules. In MPG, we proposed a powerful MolGNet model and an effective self-supervised strategy for pre-tra…
An Interpretable Framework Applying Protein Words to Predict Protein-Small Molecule Complementary Pairing Rules
MOE Key Laboratory of Bioinformatics（教育部生物信息学重点实验室）；State Key Laboratory of Molecular Oncology（分子肿瘤学国家重点实验室）；Beijing Frontier Research Center for Biological Structure（北京前沿生物结构研究中心）；School of Pharmaceutical Sciences, Tsinghua University（清华大学药学院）
Navigating Healthcare Insights: A Birds Eye View of Explainability with Knowledge Graphs
Hajim School of Engineering and Applied Sciences, University of Rochester（罗切斯特大学哈吉米工程与应用科学学院）；College of Engineering and Applied Sciences, University at Albany, State University of New York（纽约州立大学奥尔巴尼分校工程与应用科学学院）；Deloitte LLC（德勤有限责任公司）
CARE: A Lightweight Plug-in Gated Correction and Uncertainty-aware Module for Long-term Time Series Forecasting
Institute of Artificial Intelligence, University of Science and Technology Beijing（北京科技大学人工智能研究院）；Key Laboratory of Intelligent Bionic Unmanned Systems, Ministry of Education, University of Science and Technology Beijing（北京科技大学智能仿生无人系统重点实验室）；School of Artificial Intelligence, University of Science and Technology Beijing（北京科技大学人工智能学院）
Predicting drug-target interaction is key for drug discovery. Recent deep learning-based methods show promising performance but two challenges remain: (i) how to explicitly model and learn local interactions between drugs and targets for better prediction and interpretation; (ii) how to generalize prediction performance on novel drug-target pairs from different distribution. In this work, we propose DrugBAN, a deep bilinear attention network (BAN) framework with domain adaptation to explicitly learn pair-wise local interactions between drugs and targets, and adapt on out-of-distribution data. …
Drug repositioning is an attractive cost-efficient strategy for the development of treatments for human diseases. Here, we propose an interpretable model that learns disease self-representations for drug repositioning. Our self-representation model represents each disease as a linear combination of a few other diseases. We enforce proximity in the learnt representations in a way to preserve the geometric structure of the human phenome network - a domain-specific knowledge that naturally adds relational inductive bias to the disease self-representations. We prove that our method is globally opt…
Intelligent System for Automated Molecular Patent Infringement Assessment
DP Technology（深势科技）；University of Science and Technology of China（中国科学技术大学）；National University of Singapore（新加坡国立大学）；Sun Yat-Sen University（中山大学）；AI for Science Institute, Beijing（北京科学智能研究院）；Peking University（北京大学）
Washington University in St. Louis（圣路易斯华盛顿大学）；Washington University School of Medicine（华盛顿大学医学院）
We investigate molecular mechanisms of resistant or sensitive response of cancer drug combination therapies in an inductive and interpretable manner. Though deep learning algorithms are widely used in the drug synergy prediction problem, it is still an open problem to formulate the prediction model with biological meaning to investigate the mysterious mechanisms of synergy (MoS) for the human-AI collaboration in healthcare systems. To address the challenges, we propose a deep graph neural network, IDSP (Interpretable Deep Signaling Pathways), to incorporate the gene-gene as well as gene-drug r…
University of Electronic Science and Technology of China（电子科技大学）；SipingSoft Co. Ltd.（四平软件有限公司）
The drug discovery stage is a vital aspect of the drug development process and forms part of the initial stages of the development pipeline. In recent times, machine learning-based methods are actively being used to model drug-target interactions for rational drug discovery due to the successful application of these methods in other domains. In machine learning approaches, the numerical representation of molecules is critical to the performance of the model. While significant progress has been made in molecular representation engineering, this has resulted in several descriptors for both targe…
Compound-protein pairs dominate FDA-approved drug-target pairs and the prediction of compound-protein affinity and contact (CPAC) could help accelerate drug discovery. In this study we consider proteins as multi-modal data including 1D amino-acid sequences and (sequence-predicted) 2D residue-pair contact maps. We empirically evaluate the embeddings of the two single modalities in their accuracy and generalizability of CPAC prediction (i.e. structure-free interpretable compound-protein affinity prediction). And we rationalize their performances in both challenges of embedding individual modalit…
Auto-ADMET: An Effective and Interpretable AutoML Method for Chemical ADMET Property Prediction
Baker Heart and Diabetes Institute（贝克心脏与糖尿病研究所）；School of Chemistry & Molecular Biosciences, The University of Queensland（昆士兰大学化学与分子生物科学学院）；Department of Cardiometabolic Health, The University of Melbourne（墨尔本大学心脏代谢健康系）
The interpretability of deep learning models has raised extended attention these years. It will be beneficial if we can learn an interpretable structure from deep learning models. In this paper, we focus on Recurrent Neural Networks~(RNNs) especially gated RNNs whose inner mechanism is still not clearly understood. We find that Finite State Automaton~(FSA) that processes sequential data has more interpretable inner mechanism according to the definition of interpretability and can be learned from RNNs as the interpretable structure. We propose two methods to learn FSA from RNN based on two diff…
AdaptMol: Adaptive Fusion from Sequence String to Topological Structure for Few-shot Drug Discovery
College of Computer Science and Electronic Engineering, Hunan University（湖南大学计算机科学与电子工程学院）；School of Biomedical Science, Hunan University（湖南大学生物医学科学学院）
Scaling Structure Aware Virtual Screening to Billions of Molecules with SPRINT
University of Pittsburgh（匹兹堡大学）；Carnegie Mellon University（卡内基梅隆大学）；Mohamed Bin Zayed University of Artificial Intelligence（穆罕默德·本·扎耶德人工智能大学）；Petuum Inc.（Petuum公司）
A Gated Catchment Hydrology Model (GCHM) for Physically-Interpretable Rainfall-Evapotranspiration-Runoff Simulation Across Diverse Hydroclimatic Regimes
Towards Interpretable Drug-Drug Interaction Prediction: A Graph-Based Approach with Molecular and Network-Level Explanations
Data Science Institute, School of Mathematics, Shandong University（数据科学研究院、数学学院、山东大学）；Academy of Mathematics and Systems Science, Chinese Academy of Sciences（数学与系统科学研究院、中国科学院）；Data Science Institute, Shandong University（数据科学研究院、山东大学）
Diffusion models achieve state-of-the-art performance in generating realistic objects and have been successfully applied to images, text, and videos. Recent work has shown that diffusion can also be defined on graphs, including graph representations of drug-like molecules. Unfortunately, it remains difficult to perform conditional generation on graphs in a way which is interpretable and controllable. In this work, we propose GraphGUIDE, a novel framework for graph generation using diffusion models, where edges in the graph are flipped or set at each discrete time step. We demonstrate GraphGUID…
GALUX inc.（GALUX公司）；Seoul National University（首尔国立大学）
In drug discovery, aqueous solubility is an important pharmacokinetic property which affects absorption and assay availability of drug. Thus, in silico prediction of solubility has been studied for its utility in virtual screening and lead optimization. Recently, machine learning (ML) methods using experimental data has been popular because physics-based methods like quantum mechanics and molecular dynamics are not suitable for high-throughput tasks due to its computational costs. However, ML method can exhibit over-fitting problem in a data-deficient condition, and this is the case for most c…
Golisano College of Computing and Information Sciences, Rochester Institute of Technology（罗切斯特理工学院戈利萨诺计算与信息科学学院）；Thomas H. Gosnell School of Life Sciences, Rochester Institute of Technology（罗切斯特理工学院托马斯·H·戈斯内尔生命科学学院）
Predicting protein-protein interactions (PPIs) by learning informative representations from amino acid sequences is a challenging yet important problem in biology. Although various deep learning models in Siamese architecture have been proposed to model PPIs from sequences, these methods are computationally expensive for a large number of PPIs due to the pairwise encoding process. Furthermore, these methods are difficult to interpret because of non-intuitive mappings from protein sequences to their sequence representation. To address these challenges, we present a novel deep framework to model…
Concomitant administration of drugs can cause drug-drug interactions (DDIs). Some drug combinations are beneficial, but other ones may cause negative effects which are previously unrecorded. Previous works on DDI prediction usually rely on hand-engineered domain knowledge, which is laborious to obtain. In this work, we propose a novel model, Molecular Substructure-Aware Network (MSAN), to effectively predict potential DDIs from molecular structures of drug pairs. We adopt a Transformer-like substructure extraction module to acquire a fixed number of representative vectors that are associated w…
VQSynery: Robust Drug Synergy Prediction With Vector Quantization Mechanism
School of Data Science and Engineering（数据科学与工程学院）；East China Normal University（华东师范大学）；School of Medicine（医学院）；College of Design&Engineering（设计与工程学院）；National University of Singapore（新加坡国立大学）
Nara Institute of Science and Technology（奈良先端科学技术大学院大学）
Molecule property prediction is a fundamental problem for computer-aided drug discovery and materials science. Quantum-chemical simulations such as density functional theory (DFT) have been widely used for calculating the molecule properties, however, because of the heavy computational cost, it is difficult to search a huge number of potential chemical compounds. Machine learning methods for molecular modeling are attractive alternatives, however, the development of expressive, accurate, and scalable graph neural networks for learning molecular representations is still challenging. In this wor…
