Deep generative models have emerged as a powerful tool for learning useful molecular representations and designing novel molecules with desired properties, with applications in drug discovery and material design. However, most existing deep generative models are restricted due to lack of spatial information. Here we propose augmentation of deep generative models with topological data analysis (TDA) representations, known as persistence images, for robust encoding of 3D molecular geometry. We show that the TDA augmentation of a character-based Variational Auto-Encoder (VAE) outperforms state-of-the-art generative neural nets in accurately modeling the structural composition of the QM9 benchmark. Generated molecules are valid, novel, and diverse, while exhibiting distinct electronic property distribution, namely higher sample population with small HOMO-LUMO gap. These results demonstrate that TDA features indeed provide crucial geometric signal for learning abstract structures, which is non-trivial for existing generative models operating on string, graph, or 3D point sets to capture.
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）
Materials discovery is decisive for tackling urgent challenges related to energy, the environment, health care and many others. In chemistry, conventional methodologies for innovation usually rely on expensive and incremental strategies to optimize properties from molecular structures. On the other hand, inverse approaches map properties to structures, thus expediting the design of novel useful compounds. In this chapter, we examine the way in which current deep generative models are addressing the inverse chemical discovery paradigm. We begin by revisiting early inverse design algorithms. The…
Machine learning in drug discovery has been focused on virtual screening of molecular libraries using discriminative models. Generative models are an entirely different approach that learn to represent and optimize molecules in a continuous latent space. These methods have been increasingly successful at generating two dimensional molecules as SMILES strings and molecular graphs. In this work, we describe deep generative models of three dimensional molecular structures using atomic density grids and a novel fitting algorithm for converting continuous grids to discrete molecular structures. Our…
While generative models have recently become ubiquitous in many scientific areas, less attention has been paid to their evaluation. For molecular generative models, the state-of-the-art examines their output in isolation or in relation to its input. However, their biological and functional properties, such as ligand-target interaction is not being addressed. In this study, a novel biologically-inspired benchmark for the evaluation of molecular generative models is proposed. Specifically, three diverse reference datasets are designed and a set of metrics are introduced which are directly releva…
Generating molecular graphs with desired chemical properties driven by deep graph generative models provides a very promising way to accelerate drug discovery process. Such graph generative models usually consist of two steps: learning latent representations and generation of molecular graphs. However, to generate novel and chemically-valid molecular graphs from latent representations is very challenging because of the chemical constraints and combinatorial complexity of molecular graphs. In this paper, we propose MoFlow, a flow-based graph generative model to learn invertible mappings between…
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…
Searching new molecules in areas like drug discovery often starts from the core structures of candidate molecules to optimize the properties of interest. The way as such has called for a strategy of designing molecules retaining a particular scaffold as a substructure. On this account, our present work proposes a scaffold-based molecular generative model. The model generates molecular graphs by extending the graph of a scaffold through sequential additions of vertices and edges. In contrast to previous related models, our model guarantees the generated molecules to retain the given scaffold wi…
Gwangju Institute of Science and Technology（光州科学技术院）
Personalized medicine is expected to maximize the intended drug effects and minimize side effects by treating patients based on their genetic profiles. Thus, it is important to generate drugs based on the genetic profiles of diseases, especially in anticancer drug discovery. However, this is challenging because the vast chemical space and variations in cancer properties require a huge time resource to search for proper molecules. Therefore, an efficient and fast search method considering genetic profiles is required for de novo molecular design of anticancer drugs. Here, we propose a faster mo…
In the scope of drug discovery, the molecular design aims to identify novel compounds from the chemical space where the potential drug-like molecules are estimated to be in the order of 10^60 - 10^100. Since this search task is computationally intractable due to the unbounded search space, deep learning draws a lot of attention as a new way of generating unseen molecules. As we seek compounds with specific target proteins, we propose a Transformer-based deep model for de novo target-specific molecular design. The proposed method is capable of generating both drug-like compounds (without specif…
Augmenting Molecular Graphs with Geometries via Machine Learning Interatomic Potentials
Department of Computer Science & Engineering（计算机科学与工程系）；Texas A&M University（德克萨斯大学）；RIKEN Cluster for Pioneering Research, RIKEN（RIKEN先锋研究集群）；Lambda, Inc.（Lambda公司）；NVIDIA；Department of Materials Science & Engineering（材料科学与工程系）
How Molecular Generative Models Organize Molecular Identity
Toyota Research Institute（丰田研究所）；Technical University of Denmark（丹麦技术大学）；CAPeX Pioneer Center for Accelerating P2X Materials Discovery（CAPeX P2X材料发现加速先锋中心）；University of Toronto（多伦多大学）；Vector Institute for Artificial Intelligence（向量人工智能研究所）；NVIDIA（英伟达）；Massachusetts Institute of Technology（麻省理工学院）；Acceleration Consortium（加速联盟）
University of Toronto（多伦多大学）；Karlsruhe Institute of Technology（卡尔斯鲁厄理工学院）；Vector Institute for Artificial Intelligence（矢量人工智能研究所）；Canadian Institute for Advanced Research (CIFAR)（加拿大高等研究院（CIFAR））
Challenges in natural sciences can often be phrased as optimization problems. Machine learning techniques have recently been applied to solve such problems. One example in chemistry is the design of tailor-made organic materials and molecules, which requires efficient methods to explore the chemical space. We present a genetic algorithm (GA) that is enhanced with a neural network (DNN) based discriminator model to improve the diversity of generated molecules and at the same time steer the GA. We show that our algorithm outperforms other generative models in optimization tasks. We furthermore p…
Mila - Québec AI Institute（米拉-魁北克人工智能研究所）；Université de Montréal（蒙特利尔大学）；Peking University（北京大学）；Canadian Institute for Advanced Research (CIFAR)（加拿大高等研究院）；University of Illinois at Urbana-Champaign（伊利诺伊大学厄巴纳-香槟分校）；HEC Montréal（蒙特利尔高等商学院）
We study how to generate molecule conformations (i.e., 3D structures) from a molecular graph. Traditional methods, such as molecular dynamics, sample conformations via computationally expensive simulations. Recently, machine learning methods have shown great potential by training on a large collection of conformation data. Challenges arise from the limited model capacity for capturing complex distributions of conformations and the difficulty in modeling long-range dependencies between atoms. Inspired by the recent progress in deep generative models, in this paper, we propose a novel probabilis…
Seoul National University（首尔大学）；Ewha Womans University（梨花女子大学）
Discovering new materials better suited to specific purposes is an important issue in improving the quality of human life. Here, a neural network that creates molecules that meet some desired conditions based on a deep understanding of chemical language is proposed (Generative Chemical Transformer, GCT). The attention mechanism in GCT allows a deeper understanding of molecular structures beyond the limitations of chemical language itself which cause semantic discontinuity by paying attention to characters sparsely. It is investigated that the significance of language models for inverse molecul…
Deep generative models have been applied with increasing success to the generation of two dimensional molecules as SMILES strings and molecular graphs. In this work we describe for the first time a deep generative model that can generate 3D molecular structures conditioned on a three-dimensional (3D) binding pocket. Using convolutional neural networks, we encode atomic density grids into separate receptor and ligand latent spaces. The ligand latent space is variational to support sampling of new molecules. A decoder network generates atomic densities of novel ligands conditioned on the recepto…
Energy-Guided Generative Modeling for Low-Energy Molecular Structure Discovery
School of Artificial Intelligence, Shanghai Jiao Tong University（上海交通大学人工智能学院）；Department of Computer Science, National University of Singapore（新加坡国立大学计算机科学系）；Shenzhen International Graduate School, Tsinghua University（清华大学深圳国际研究生院）
Deep generative models are attracting great attention as a new promising approach for molecular design. All models reported so far are based on either variational autoencoder (VAE) or generative adversarial network (GAN). Here we propose a new type model based on an adversarially regularized autoencoder (ARAE). It basically uses latent variables like VAE, but the distribution of the latent variables is obtained by adversarial training like in GAN. The latter is intended to avoid both inappropriate approximation of posterior distribution in VAE and difficulty in handling discrete variables in G…
Looking Under the Streetlight: Evaluation in Generative Molecular Dynamics
Chalmers University of Technology and University of Gothenburg（查尔姆斯理工大学和哥德堡大学）；Microsoft Research Berlin（微软研究院柏林）；Stanford University（斯坦福大学）；University of Copenhagen（哥本哈根大学）
Intermolecular and long-range interactions are central to phenomena as diverse as gene regulation, topological states of quantum materials, electrolyte transport in batteries, and the universal solvation properties of water. We present a set of challenge problems for preserving intermolecular interactions and structural motifs in machine-learning approaches to chemical problems, through the use of a recently published dataset of 4.95 million water clusters held together by hydrogen bonding interactions and resulting in longer range structural patterns. The dataset provides spatial coordinates …
Technische Universität Berlin（柏林工业大学）；Berlin Institute for the Foundations of Learning and Data（柏林学习与数据基础研究所）；Korea University（高丽大学）；Max-Planck-Institut für Informatik（马克斯·普朗克信息学研究所）
The rational design of molecules with desired properties is a long-standing challenge in chemistry. Generative neural networks have emerged as a powerful approach to sample novel molecules from a learned distribution. Here, we propose a conditional generative neural network for 3d molecular structures with specified chemical and structural properties. This approach is agnostic to chemical bonding and enables targeted sampling of novel molecules from conditional distributions, even in domains where reference calculations are sparse. We demonstrate the utility of our method for inverse design by…
Massachusetts Institute of Technology（麻省理工学院）；Mila - Québec AI Institute（米拉-魁北克人工智能研究所）；Universite de Montréal（蒙特利尔大学）；University of California San Diego（加州大学圣地亚哥分校）；University of Amsterdam（阿姆斯特丹大学）；HEC Montréal（蒙特利尔高等商学院）；CIFAR AI Chair（加拿大高等研究院人工智能讲席）
Coarse-graining (CG) of molecular simulations simplifies the particle representation by grouping selected atoms into pseudo-beads and drastically accelerates simulation. However, such CG procedure induces information losses, which makes accurate backmapping, i.e., restoring fine-grained (FG) coordinates from CG coordinates, a long-standing challenge. Inspired by the recent progress in generative models and equivariant networks, we propose a novel model that rigorously embeds the vital probabilistic nature and geometric consistency requirements of the backmapping transformation. Our model encod…
UC Berkeley（加州大学伯克利分校）；MIT（麻省理工学院）；University of Cambridge（剑桥大学）
Generative models in molecular design tend to be richly parameterized, data-hungry neural models, as they must create complex structured objects as outputs. Estimating such models from data may be challenging due to the lack of sufficient training data. In this paper, we propose a surprisingly effective self-training approach for iteratively creating additional molecular targets. We first pre-train the generative model together with a simple property predictor. The property predictor is then used as a likelihood model for filtering candidate structures from the generative model. Additional tar…
Designing a molecule with desired properties is one of the biggest challenges in drug development, as it requires optimization of chemical compound structures with respect to many complex properties. To augment the compound design process we introduce Mol-CycleGAN - a CycleGAN-based model that generates optimized compounds with high structural similarity to the original ones. Namely, given a molecule our model generates a structurally similar one with an optimized value of the considered property. We evaluate the performance of the model on selected optimization objectives related to structura…
Recent advances in artificial intelligence have propelled the development of innovative computational materials modeling and design techniques. Generative deep learning models have been used for molecular representation, discovery, and design. In this work, we assess the predictive capabilities of a molecular generative model developed based on variational inference and graph theory in the small data regime. Physical constraints that encourage energetically stable molecules are proposed. The encoding network is based on the scattering transform with adaptive spectral filters to allow for bette…
The design of molecules and materials with tailored properties is challenging, as candidate molecules must satisfy multiple competing requirements that are often difficult to measure or compute. While molecular structures, produced through generative deep learning, will satisfy those patterns, they often only possess specific target properties by chance and not by design, which makes molecular discovery via this route inefficient. In this work, we predict molecules with (pareto)-optimal properties by combining a generative deep learning model that predicts three dimensional conformations of mo…
