Properties of molecules are indicative of their functions and thus are useful in many applications. With the advances of deep learning methods, computational approaches for predicting molecular properties are gaining increasing momentum. However, there lacks customized and advanced methods and comprehensive tools for this task currently. Here we develop a suite of comprehensive machine learning methods and tools spanning different computational models, molecular representations, and loss functions for molecular property prediction and drug discovery. Specifically, we represent molecules as both graphs and sequences. Built on these representations, we develop novel deep models for learning from molecular graphs and sequences. In order to learn effectively from highly imbalanced datasets, we develop advanced loss functions that optimize areas under precision-recall curves. Altogether, our work not only serves as a comprehensive tool, but also contributes towards developing novel and advanced graph and sequence learning methodologies. Results on both online and offline antibiotics discovery and molecular property prediction tasks show that our methods achieve consistent improvements over prior methods. In particular, our methods achieve #1 ranking in terms of both ROC-AUC and PRC-AUC on the AI Cures Open Challenge for drug discovery related to COVID-19. Our software is released as part of the MoleculeX library under AdvProp.
Peking University（北京大学）；School of Pharmaceutical Sciences, Peking University（北京大学药学院）
The ultimate goal of drug design is to find novel compounds with desirable pharmacological properties. Designing molecules retaining particular scaffolds as the core structures of the molecules is one of the efficient ways to obtain potential drug candidates with desirable properties. We proposed a scaffold-based molecular generative model for scaffold-based drug discovery, which performs molecule generation based on a wide spectrum of scaffold definitions, including BM-scaffolds, cyclic skeletons, as well as scaffolds with specifications on side-chain properties. The model can generalize the …
Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences（中国科学院深圳先进技术研究院）
Drug discovery is vitally important for protecting human against disease. Target-based screening is one of the most popular methods to develop new drugs in the past several decades. This method efficiently screens candidate drugs inhibiting target protein in vitro, but it often fails due to inadequate activity of the selected drugs in vivo. Accurate computational methods are needed to bridge this gap. Here, we propose a novel graph multi task deep learning model to identify compounds carrying both target inhibitory and cell active (MATIC) properties. On a carefully curated SARS-CoV-2 dataset, …
Drug targets are the main focus of drug discovery due to their key role in disease pathogenesis. Computational approaches are widely applied to drug development because of the increasing availability of biological molecular datasets. Popular generative approaches can create new drug molecules by learning the given molecule distributions. However, these approaches are mostly not for target-specific drug discovery. We developed an energy-based probabilistic model for computational target-specific drug discovery. Results show that our proposed TagMol can generate molecules with similar binding af…
Relation Therapeutics（Relay Therapeutics（注：原文为Relation Therapeutics，直译：关系治疗公司））；University of Cambridge（剑桥大学）；Juvenescence（Juvenescence公司）；Mila, the Quebec AI Institute（米拉魁北克人工智能研究所）；HEC Montreal（蒙特利尔高等商学院）；The Francis Crick Institute（弗朗西斯·克里克研究所）；Imperial College London（帝国理工学院）；Twitter（推特）
Graph Machine Learning (GML) is receiving growing interest within the pharmaceutical and biotechnology industries for its ability to model biomolecular structures, the functional relationships between them, and integrate multi-omic datasets - amongst other data types. Herein, we present a multidisciplinary academic-industrial review of the topic within the context of drug discovery and development. After introducing key terms and modelling approaches, we move chronologically through the drug development pipeline to identify and summarise work incorporating: target identification, design of sma…
European Molecular Biology Laboratory（欧洲分子生物学实验室）；European Bioinformatics Institute（欧洲生物信息研究所）；University of Cambridge（剑桥大学）
Estimating the reliability of individual predictions is key to increase the adoption of computational models and artificial intelligence in preclinical drug discovery, as well as to foster its application to guide decision making in clinical settings. Among the large number of algorithms developed over the last decades to compute prediction errors, Conformal Prediction (CP) has gained increasing attention in the computational drug discovery community. A major reason for its recent popularity is the ease of interpretation of the computed prediction errors in both classification and regression t…
Department of Computer and Data Sciences, Case Western Reserve University（计算机与数据科学系，凯斯西储大学）；Case Western Reserve University（凯斯西储大学）；Department of Biochemistry, Case Western Reserve University（生物化学系，凯斯西储大学）；Center for RNA Science and Therapeutics, Case Western Reserve University（RNA科学与治疗中心，凯斯西储大学）；Department of Biomedical Engineering, Case Western Reserve University（生物医学工程系，凯斯西储大学）
The de novo design of molecular structures using deep learning generative models introduces an encouraging solution to drug discovery in the face of the continuously increased cost of new drug development. From the generation of original texts, images, and videos, to the scratching of novel molecular structures, the incredible creativity of deep learning generative models surprised us about the height machine intelligence can achieve. The purpose of this paper is to review the latest advances in generative chemistry which relies on generative modeling to expedite the drug discovery process. Th…
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…
Chalmers University of Technology（查尔姆斯理工大学）；AstraZeneca AB（阿斯利康公司）
We study the problem of performing automated experiment design for drug screening through Bayesian inference and optimisation. In particular, we compare and contrast the behaviour of linear-Gaussian models and Gaussian processes, when used in conjunction with upper confidence bound algorithms, Thompson sampling, or bounded horizon tree search. We show that non-myopic sophisticated exploration techniques using sparse tree search have a distinct advantage over methods such as Thompson sampling or upper confidence bounds in this setting. We demonstrate the significant superiority of the approach …
Eindhoven University of Technology（埃因霍温理工大学）；Microsoft Research Cambridge（微软剑桥研究院）；Centre for Living Technologies（生命技术中心）
Artificial intelligence (AI) in the form of deep learning bears promise for drug discovery and chemical biology, $\textit{e.g.}$, to predict protein structure and molecular bioactivity, plan organic synthesis, and design molecules $\textit{de novo}$. While most of the deep learning efforts in drug discovery have focused on ligand-based approaches, structure-based drug discovery has the potential to tackle unsolved challenges, such as affinity prediction for unexplored protein targets, binding-mechanism elucidation, and the rationalization of related chemical kinetic properties. Advances in dee…
Computational drug discovery strategies can be broadly placed in two categories: ligand-based methods which identify novel molecules by similarity with known ligands, and structure-based methods which predict molecules with high-affinity to a given 3D structure (e.g. a protein). However, ligand-based methods do not leverage information about the binding site, and structure-based approaches rely on the knowledge of a finite set of ligands binding the target. In this work, we introduce TarLig, a novel approach that aims to bridge the gap between ligand and structure-based approaches. We use the …
Artificial intelligence (AI) has been transforming the practice of drug discovery in the past decade. Various AI techniques have been used in a wide range of applications, such as virtual screening and drug design. In this survey, we first give an overview on drug discovery and discuss related applications, which can be reduced to two major tasks, i.e., molecular property prediction and molecule generation. We then discuss common data resources, molecule representations and benchmark platforms. Furthermore, to summarize the progress of AI in drug discovery, we present the relevant AI technique…
DrugPlayGround: Benchmarking Large Language Models and Embeddings for Drug Discovery
Yale University（耶鲁大学）；Broad Institute of MIT and Harvard（麻省理工学院和哈佛大学博德研究所）；The Chinese University of Hong Kong（香港中文大学）；University of California, Berkeley（加州大学伯克利分校）；UC Berkeley（加州大学伯克利分校）
Technion - Israel Institute of Technology（以色列理工学院）
Designing a new drug is a lengthy and expensive process. As the space of potential molecules is very large (10^23-10^60), a common technique during drug discovery is to start from a molecule which already has some of the desired properties. An interdisciplinary team of scientists generates hypothesis about the required changes to the prototype. In this work, we develop an algorithmic unsupervised-approach that automatically generates potential drug molecules given a prototype drug. We show that the molecules generated by the system are valid molecules and significantly different from the proto…
Mila - Quebec AI Institute（米拉-魁北克人工智能研究所）；University of Montreal（蒙特利尔大学）；Peking University（北京大学）；Shanghai Jiao Tong University（上海交通大学）；Tsinghua University（清华大学）
Machine learning has huge potential to revolutionize the field of drug discovery and is attracting increasing attention in recent years. However, lacking domain knowledge (e.g., which tasks to work on), standard benchmarks and data preprocessing pipelines are the main obstacles for machine learning researchers to work in this domain. To facilitate the progress of machine learning for drug discovery, we develop TorchDrug, a powerful and flexible machine learning platform for drug discovery built on top of PyTorch. TorchDrug benchmarks a variety of important tasks in drug discovery, including mo…
Drug discovery aims at designing novel molecules with specific desired properties for clinical trials. Over past decades, drug discovery and development have been a costly and time consuming process. Driven by big chemical data and AI, deep generative models show great potential to accelerate the drug discovery process. Existing works investigate different deep generative frameworks for molecular generation, however, less attention has been paid to the visualization tools to quickly demo and evaluate model's results. Here, we propose a visualization framework which provides interactive visuali…
BME（布达佩斯技术与经济大学）；University of Cambridge（剑桥大学）；KUL（鲁汶大学）；Owkin（Owkin公司）
Pharmaceutical industry can better leverage its data assets to virtualize drug discovery through a collaborative machine learning platform. On the other hand, there are non-negligible risks stemming from the unintended leakage of participants' training data, hence, it is essential for such a platform to be secure and privacy-preserving. This paper describes a privacy risk assessment for collaborative modeling in the preclinical phase of drug discovery to accelerate the selection of promising drug candidates. After a short taxonomy of state-of-the-art inference attacks we adopt and customize se…
Massachusetts Institute of Technology（麻省理工学院）；Stanford University（斯坦福大学）
Recent advances in machine learning have made significant contributions to drug discovery. Deep neural networks in particular have been demonstrated to provide significant boosts in predictive power when inferring the properties and activities of small-molecule compounds. However, the applicability of these techniques has been limited by the requirement for large amounts of training data. In this work, we demonstrate how one-shot learning can be used to significantly lower the amounts of data required to make meaningful predictions in drug discovery applications. We introduce a new architectur…
DrugGen 2: A disease-aware language model for enhancing drug discovery
Regenerative Medicine Research Center（再生医学研究中心）；Isfahan University of Medical Sciences（伊斯法罕医科大学）；Isfahan Neuroscience Research Center（伊斯法罕神经科学研究中心）；School of Pharmacy（药学院）；Department of Medicinal Chemistry（药理化学系）；Cardiovascular Research Institute（心血管研究学院）；Department of Genetics and Molecular Biology（基因与分子生物学系）；Bioinformatics Research Center（生物信息学研究中心）
This paper explores conformal prediction in the learning under privileged information (LUPI) paradigm. We use the SVM+ realization of LUPI in an inductive conformal predictor, and apply it to the MNIST benchmark dataset and three datasets in drug discovery. The results show that using privileged information produces valid models and improves efficiency compared to standard SVM, however the improvement varies between the tested datasets and is not substantial in the drug discovery applications. More importantly, using SVM+ in a conformal prediction framework enables valid prediction intervals a…
REINFORCE-ING Chemical Language Models for Drug Discovery
Computational Science Laboratory, Universitat Pompeu Fabra, Barcelona Biomedical Research Park (PRBB), C Dr. Aiguader 88, 08003 Barcelona, Spain；In Silico Discovery, Janssen Research \& Development, Janssen Pharmaceutica N. V., Turnhoutseweg 30, B-2340 Beerse, Belgium
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）
Penn State University（宾夕法尼亚州立大学）；Penn State College of Medicine（宾夕法尼亚州立大学医学院）
Traditional drug discovery pipeline takes several years and cost billions of dollars. Deep generative and predictive models are widely adopted to assist in drug development. Classical machines cannot efficiently produce atypical patterns of quantum computers which might improve the training quality of learning tasks. We propose a suite of quantum machine learning techniques e.g., generative adversarial network (GAN), convolutional neural network (CNN) and variational auto-encoder (VAE) to generate small drug molecules, classify binding pockets in proteins, and generate large drug molecules, re…
Previous work established skip-gram word2vec models could be used to mine knowledge in the materials science literature for the discovery of thermoelectrics. Recent transformer architectures have shown great progress in language modeling and associated fine-tuned tasks, but they have yet to be adapted for drug discovery. We present a RoBERTa transformer-based method that extends the masked language token prediction using query-target conditioning to treat the specificity challenge. The transformer discovery method entails several benefits over the word2vec method including domain-specific (ant…
Models that accurately predict properties based on chemical structure are valuable tools in drug discovery. However, for many properties, public and private training sets are typically small, and it is difficult for the models to generalize well outside of the training data. Recently, large language models have addressed this problem by using self-supervised pretraining on large unlabeled datasets, followed by fine-tuning on smaller, labeled datasets. In this paper, we report MolE, a molecular foundation model that adapts the DeBERTa architecture to be used on molecular graphs together with a …
Augmenting generative models with biomedical knowledge graphs improves targeted drug discovery
Edwardson School of Industrial Engineering and the Institute of Cancer Research, Purdue University（埃德沃兹工业工程学院和癌症研究所，普渡大学）；Elmore Family School of Electrical and Computer Engineering, Purdue University（埃尔摩家庭电气与计算机工程学院，普渡大学）
Ping An Healthcare Technology（平安医疗科技）；Chinese Academy of Medical Sciences（中国医学科学院）；National Cancer Center（国家癌症中心）；Xidian University School of Computer Science and Technology（西安电子科技大学计算机科学与技术学院）
Anti-cancer drug discoveries have been serendipitous, we sought to present the Open Molecular Graph Learning Benchmark, named CandidateDrug4Cancer, a challenging and realistic benchmark dataset to facilitate scalable, robust, and reproducible graph machine learning research for anti-cancer drug discovery. CandidateDrug4Cancer dataset encompasses multiple most-mentioned 29 targets for cancer, covering 54869 cancer-related drug molecules which are ranged from pre-clinical, clinical and FDA-approved. Besides building the datasets, we also perform benchmark experiments with effective Drug Target I…
Tencent AI Lab（腾讯人工智能实验室）；The Chinese University of Hong Kong（香港中文大学）；Tsinghua University（清华大学）；Hong Kong University of Science and Technology (Guangzhou)（香港科技大学（广州））；Hong Kong University of Science and Technology（香港科技大学）；Renmin University of China（中国人民大学）；University of Science and Technology of China（中国科学技术大学）
The last decade has witnessed a prosperous development of computational methods and dataset curation for AI-aided drug discovery (AIDD). However, real-world pharmaceutical datasets often exhibit highly imbalanced distribution, which is overlooked by the current literature but may severely compromise the fairness and generalization of machine learning applications. Motivated by this observation, we introduce ImDrug, a comprehensive benchmark with an open-source Python library which consists of 4 imbalance settings, 11 AI-ready datasets, 54 learning tasks and 16 baseline algorithms tailored for …
Background. The Drug Discovery Unit (DDU) of Cancer Research UK (CRUK) is using the software Dotmatics for storage and analysis of scientific data during drug discovery process. Whilst the data include event logs, time stamps, activities, and user information are mostly sitting in the database without fully utilising their potential value. Aims. This dissertation aims at extracting knowledge from event logs data which recorded during drug discovery process, to capture the operational business process of the DDU of Cancer Research UK (CRUK) as it was being executed. It provides the evaluations …
University College London（伦敦大学学院）；Università di Napoli Federico II（那不勒斯费德里科二世大学）；University of Chicago（芝加哥大学）；RWTH Aachen University（亚琛工业大学）；Brookhaven National Laboratory（布鲁克海文国家实验室）；Rutgers, the State University of New Jersey（罗格斯大学，新泽西州立大学）；Science Museum（科学博物馆）；Italian Institute of Technology（意大利理工学院）；Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences and Humanities（巴伐利亚科学与人文学院莱布尼茨超级计算中心）；CERN（欧洲核子研究中心）；Argonne National Laboratory（阿贡国家实验室）；University of Amsterdam（阿姆斯特丹大学）
The race to meet the challenges of the global pandemic has served as a reminder that the existing drug discovery process is expensive, inefficient and slow. There is a major bottleneck screening the vast number of potential small molecules to shortlist lead compounds for antiviral drug development. New opportunities to accelerate drug discovery lie at the interface between machine learning methods, in this case developed for linear accelerators, and physics-based methods. The two in silico methods, each have their own advantages and limitations which, interestingly, complement each other. Here…
D. E. Shaw Research（D.E.肖研究所）；Columbia University（哥伦比亚大学）
Drug discovery projects entail cycles of design, synthesis, and testing that yield a series of chemically related small molecules whose properties, such as binding affinity to a given target protein, are progressively tailored to a particular drug discovery goal. The use of deep learning technologies could augment the typical practice of using human intuition in the design cycle, and thereby expedite drug discovery projects. Here we present DESMILES, a deep neural network model that advances the state of the art in machine learning approaches to molecular design. We applied DESMILES to a previ…
Virus infection is one of the major diseases that seriously threaten human health. To meet the growing demand for mining and sharing data resources related to antiviral drugs and to accelerate the design and discovery of new antiviral drugs, we presented an open-access antiviral drug resource and machine learning platform (VDDB), which, to the best of our knowledge, is the first comprehensive dedicated resource for experimentally verified potential drugs/molecules based on manually curated data. Currently, VDDB highlights 848 clinical vaccines, 199 clinical antibodies, as well as over 710,000 …
Rensselaer Polytechnic Institute（拉特格斯理工大学）；University of Illinois at Urbana-Champaign（伊利诺伊大学厄巴纳-香槟分校）；University of Pittsburgh（匹兹堡大学）；University of Chicago（芝加哥大学）；Novo Nordisk A/S（诺和制药）；Harvard University（哈佛大学）
Generating molecules with desired chemical properties is important for drug discovery. The use of generative neural networks is promising for this task. However, from visual inspection, it often appears that generated samples lack diversity. In this paper, we quantify this internal chemical diversity, and we raise the following challenge: can a nontrivial AI model reproduce natural chemical diversity for desired molecules? To illustrate this question, we consider two generative models: a Reinforcement Learning model and the recently introduced ORGAN. Both fail at this challenge. We hope this c…
Zhejiang University（浙江大学）；University of Illinois at Urbana-Champaign（伊利诺伊大学厄巴纳-香槟分校）；Hangzhou Dianzi University（杭州电子科技大学）
With the development of computer-assisted techniques, research communities including biochemistry and deep learning have been devoted into the drug discovery field for over a decade. Various applications of deep learning have drawn great attention in drug discovery, such as molecule generation, molecular property prediction, retrosynthesis prediction, and reaction prediction. While most existing surveys only focus on one of the applications, limiting the view of researchers in the community. In this paper, we present a comprehensive review on the aforementioned four aspects, and discuss the re…
Deep learning bears promise for drug discovery, including advanced image analysis, prediction of molecular structure and function, and automated generation of innovative chemical entities with bespoke properties. Despite the growing number of successful prospective applications, the underlying mathematical models often remain elusive to interpretation by the human mind. There is a demand for 'explainable' deep learning methods to address the need for a new narrative of the machine language of the molecular sciences. This review summarizes the most prominent algorithmic concepts of explainable …
FusionDTI: Fine-grained Binding Discovery with Token-level Fusion for Drug-Target Interaction
School of Computing Science（计算科学学院）；School of Cancer Sciences（癌症科学学院）；Cancer Research UK Scotland Institute（英国癌症研究苏格兰研究所）；University of Glasgow（格拉斯哥大学）
Predicating macroscopic influences of drugs on human body, like efficacy and toxicity, is a central problem of small-molecule based drug discovery. Molecules can be represented as an undirected graph, and we can utilize graph convolution networks to predication molecular properties. However, graph convolutional networks and other graph neural networks all focus on learning node-level representation rather than graph-level representation. Previous works simply sum all feature vectors for all nodes in the graph to obtain the graph feature vector for drug predication. In this paper, we introduce …
