The task of learning an expressive molecular representation is central to developing quantitative structure–activity and property relationships. Traditional approaches rely on group additivity rules, ...empirical measurements or parameters, or generation of thousands of descriptors. In this paper, we employ a convolutional neural network for this embedding task by treating molecules as undirected graphs with attributed nodes and edges. Simple atom and bond attributes are used to construct atom-specific feature vectors that take into account the local chemical environment using different neighborhood radii. By working directly with the full molecular graph, there is a greater opportunity for models to identify important features relevant to a prediction task. Unlike other graph-based approaches, our atom featurization preserves molecule-level spatial information that significantly enhances model performance. Our models learn to identify important features of atom clusters for the prediction of aqueous solubility, octanol solubility, melting point, and toxicity. Extensions and limitations of this strategy are discussed.
We present a supervised learning approach to predict the products of organic reactions given their reactants, reagents, and solvent(s). The prediction task is factored into two stages comparable to ...manual expert approaches: considering possible sites of reactivity and evaluating their relative likelihoods. By training on hundreds of thousands of reaction precedents covering a broad range of reaction types from the patent literature, the neural model makes informed predictions of chemical reactivity. The model predicts the major product correctly over 85% of the time requiring around 100 ms per example, a significantly higher accuracy than achieved by previous machine learning approaches, and performs on par with expert chemists with years of formal training. We gain additional insight into predictions
the design of the neural model, revealing an understanding of chemistry qualitatively consistent with manual approaches.
Due to the rapid emergence of antibiotic-resistant bacteria, there is a growing need to discover new antibiotics. To address this challenge, we trained a deep neural network capable of predicting ...molecules with antibacterial activity. We performed predictions on multiple chemical libraries and discovered a molecule from the Drug Repurposing Hub—halicin—that is structurally divergent from conventional antibiotics and displays bactericidal activity against a wide phylogenetic spectrum of pathogens including Mycobacterium tuberculosis and carbapenem-resistant Enterobacteriaceae. Halicin also effectively treated Clostridioides difficile and pan-resistant Acinetobacter baumannii infections in murine models. Additionally, from a discrete set of 23 empirically tested predictions from >107 million molecules curated from the ZINC15 database, our model identified eight antibacterial compounds that are structurally distant from known antibiotics. This work highlights the utility of deep learning approaches to expand our antibiotic arsenal through the discovery of structurally distinct antibacterial molecules.
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•A deep learning model is trained to predict antibiotics based on structure•Halicin is predicted as an antibacterial molecule from the Drug Repurposing Hub•Halicin shows broad-spectrum antibiotic activities in mice•More antibiotics with distinct structures are predicted from the ZINC15 database
A trained deep neural network predicts antibiotic activity in molecules that are structurally different from known antibiotics, among which Halicin exhibits efficacy against broad-spectrum bacterial infections in mice.
Computer assistance in synthesis design has existed for over 40 years, yet retrosynthesis planning software has struggled to achieve widespread adoption. One critical challenge in developing ...high-quality pathway suggestions is that proposed reaction steps often fail when attempted in the laboratory, despite initially seeming viable. The true measure of success for any synthesis program is whether the predicted outcome matches what is observed experimentally. We report a model framework for anticipating reaction outcomes that combines the traditional use of reaction templates with the flexibility in pattern recognition afforded by neural networks. Using 15 000 experimental reaction records from granted United States patents, a model is trained to select the major (recorded) product by ranking a self-generated list of candidates where one candidate is known to be the major product. Candidate reactions are represented using a unique edit-based representation that emphasizes the fundamental transformation from reactants to products, rather than the constituent molecules’ overall structures. In a 5-fold cross-validation, the trained model assigns the major product rank 1 in 71.8% of cases, rank ≤3 in 86.7% of cases, and rank ≤5 in 90.8% of cases.
Significance
COVID-19 has caused more than 2.5 million deaths worldwide. It is imperative that we develop therapies that can mitigate the effect of the disease. While searching for individual drugs ...for this purpose has been met with difficulties, synergistic drug combinations offer a promising alternative. However, the lack of high-quality training data pertaining to drug combinations makes it challenging to use existing machine learning methods for effective novel combination prediction tasks. Our proposed approach addresses this challenge by leveraging additional readily available data, such as drug−target interactions, thus enabling an effective in silico search for synergistic combinations against SARS-CoV-2.
Effective treatments for COVID-19 are urgently needed. However, discovering single-agent therapies with activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been challenging. Combination therapies play an important role in antiviral therapies, due to their improved efficacy and reduced toxicity. Recent approaches have applied deep learning to identify synergistic drug combinations for diseases with vast preexisting datasets, but these are not applicable to new diseases with limited combination data, such as COVID-19. Given that drug synergy often occurs through inhibition of discrete biological targets, here we propose a neural network architecture that jointly learns drug−target interaction and drug−drug synergy. The model consists of two parts: a drug−target interaction module and a target−disease association module. This design enables the model to utilize drug−target interaction data and single-agent antiviral activity data, in addition to available drug−drug combination datasets, which may be small in nature. By incorporating additional biological information, our model performs significantly better in synergy prediction accuracy than previous methods with limited drug combination training data. We empirically validated our model predictions and discovered two drug combinations, remdesivir and reserpine as well as remdesivir and IQ-1S, which display strong antiviral SARS-CoV-2 synergy in vitro. Our approach, which was applied here to address the urgent threat of COVID-19, can be readily extended to other diseases for which a dearth of chemical−chemical combination data exists.
There has been considerable recent progress in designing new proteins using deep-learning methods
. Despite this progress, a general deep-learning framework for protein design that enables solution ...of a wide range of design challenges, including de novo binder design and design of higher-order symmetric architectures, has yet to be described. Diffusion models
have had considerable success in image and language generative modelling but limited success when applied to protein modelling, probably due to the complexity of protein backbone geometry and sequence-structure relationships. Here we show that by fine-tuning the RoseTTAFold structure prediction network on protein structure denoising tasks, we obtain a generative model of protein backbones that achieves outstanding performance on unconditional and topology-constrained protein monomer design, protein binder design, symmetric oligomer design, enzyme active site scaffolding and symmetric motif scaffolding for therapeutic and metal-binding protein design. We demonstrate the power and generality of the method, called RoseTTAFold diffusion (RFdiffusion), by experimentally characterizing the structures and functions of hundreds of designed symmetric assemblies, metal-binding proteins and protein binders. The accuracy of RFdiffusion is confirmed by the cryogenic electron microscopy structure of a designed binder in complex with influenza haemagglutinin that is nearly identical to the design model. In a manner analogous to networks that produce images from user-specified inputs, RFdiffusion enables the design of diverse functional proteins from simple molecular specifications.
We develop and analyze methods for computing provably optimal maximum a posteriori probability (MAP) configurations for a subclass of Markov random fields defined on graphs with cycles. By ...decomposing the original distribution into a convex combination of tree-structured distributions, we obtain an upper bound on the optimal value of the original problem (i.e., the log probability of the MAP assignment) in terms of the combined optimal values of the tree problems. We prove that this upper bound is tight if and only if all the tree distributions share an optimal configuration in common. An important implication is that any such shared configuration must also be a MAP configuration for the original distribution. Next we develop two approaches to attempting to obtain tight upper bounds: a) a tree-relaxed linear program (LP), which is derived from the Lagrangian dual of the upper bounds; and b) a tree-reweighted max-product message-passing algorithm that is related to but distinct from the max-product algorithm. In this way, we establish a connection between a certain LP relaxation of the mode-finding problem and a reweighted form of the max-product (min-sum) message-passing algorithm.
Diffusion models in protein structure and docking Yim, Jason; Stärk, Hannes; Corso, Gabriele ...
Wiley interdisciplinary reviews. Computational molecular science,
March/April 2024, 2024-03-00, 20240301, Letnik:
14, Številka:
2
Journal Article
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Generative AI is rapidly transforming the frontier of research in computational structural biology. Indeed, recent successes have substantially advanced protein design and drug discovery. One of the ...key methodologies underlying these advances is diffusion models (DM). Diffusion models originated in computer vision, rapidly taking over image generation and offering superior quality and performance. These models were subsequently extended and modified for uses in other areas including computational structural biology. DMs are well equipped to model high dimensional, geometric data while exploiting key strengths of deep learning. In structural biology, for example, they have achieved state‐of‐the‐art results on protein 3D structure generation and small molecule docking. This review covers the basics of diffusion models, associated modeling choices regarding molecular representations, generation capabilities, prevailing heuristics, as well as key limitations and forthcoming refinements. We also provide best practices around evaluation procedures to help establish rigorous benchmarking and evaluation. The review is intended to provide a fresh view into the state‐of‐the‐art as well as highlight its potentials and current challenges of recent generative techniques in computational structural biology.
This article is categorized under:
Data Science > Artificial Intelligence/Machine Learning
Structure and Mechanism > Molecular Structures
Software > Molecular Modeling
Applications in structural biology where diffusion models are state‐of‐the‐art. We illustrate diffusion processes comprised of a forward (noising) and reverse (sampling) direction. The diffusion process starts (t=1$$ t=1 $$) with an the easy‐to‐sample noise distribution where the diffusion model guides the process to data (t=0$$ t=0 $$). Protein design conditions the protein generation on a single or multiple properties the protein must possess, for example, binding to another protein as shown. Protein–ligand docking generates multiple ligands to find the best docked pose on a protein, a crucial step in virtual screening for drug discovery.
A closed-loop, autonomous molecular discovery platform driven by integrated machine learning tools was developed to accelerate the design of molecules with desired properties. We demonstrated two ...case studies on dye-like molecules, targeting absorption wavelength, lipophilicity, and photooxidative stability. In the first study, the platform experimentally realized 294 unreported molecules across three automatic iterations of molecular design-make-test-analyze cycles while exploring the structure-function space of four rarely reported scaffolds. In each iteration, the property prediction models that guided exploration learned the structure-property space of diverse scaffold derivatives, which were realized with multistep syntheses and a variety of reactions. The second study exploited property models trained on the explored chemical space and previously reported molecules to discover nine top-performing molecules within a lightly explored structure-property space.
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