Protein-Ligand Scoring with Convolutional Neural Networks.

Computational approaches to drug discovery can reduce the time and cost associated with experimental assays and enable the screening of novel chemotypes. Structure-based drug design methods rely on scoring functions to rank and predict binding affinities and poses. The ever-expanding amount of protein-ligand binding and structural data enables the use of deep machine learning techniques for protein-ligand scoring. We describe convolutional neural network (CNN) scoring functions that take as input a comprehensive three-dimensional (3D) representation of a protein-ligand interaction. A CNN scoring function automatically learns the key features of protein-ligand interactions that correlate with binding. We train and optimize our CNN scoring functions to discriminate between correct and incorrect binding poses and known binders and nonbinders. We find that our CNN scoring function outperforms the AutoDock Vina scoring function when ranking poses both for pose prediction and virtual screening.

A D3R prospective evaluation of machine learning for protein-ligand scoring.

We assess the performance of several machine learning-based scoring methods at protein-ligand pose prediction, virtual screening, and binding affinity prediction. The methods and the manner in which they were trained make them sufficiently diverse to evaluate the utility of various strategies for training set curation and binding pose generation, but they share a novel approach to classification in the context of protein-ligand scoring. Rather than explicitly using structural data such as affinity values or information extracted from crystal binding poses for training, we instead exploit the abundance of data available from high-throughput screening to approach the problem as one of discriminating binders from non-binders. We evaluate the performance of our various scoring methods in the 2015 D3R Grand Challenge and find that although the merits of some features of our approach remain inconclusive, our scoring methods performed comparably to a state-of-the-art scoring function that was fit to binding affinity data.

Physics-Informed Neural Networks for Tissue Elasticity Reconstruction in Magnetic Resonance Elastography.

Magnetic resonance elastography (MRE) is a medical imaging modality that non-invasively quantifies tissue stiffness (elasticity) and is commonly used for diagnosing liver fibrosis. Constructing an elasticity map of tissue requires solving an inverse problem involving a partial differential equation (PDE). Current numerical techniques to solve the inverse problem are noise-sensitive and require explicit specification of physical relationships. In this work, we apply physics-informed neural networks to solve the inverse problem of tissue elasticity reconstruction. Our method does not rely on numerical differentiation and can be extended to learn relevant correlations from anatomical images while respecting physical constraints. We evaluate our approach on simulated data and in vivo data from a cohort of patients with non-alcoholic fatty liver disease (NAFLD). Compared to numerical baselines, our method is more robust to noise and more accurate on realistic data, and its performance is further enhanced by incorporating anatomical information.

Generating 3D molecules conditional on receptor binding sites with deep generative models.

The goal of structure-based drug discovery is to find small molecules that bind to a given target protein. Deep learning has been used to generate drug-like molecules with certain cheminformatic properties, but has not yet been applied to generating 3D molecules predicted to bind to proteins by sampling the conditional distribution of protein-ligand binding interactions. In this work, we describe for the first time a deep learning system for generating 3D molecular structures conditioned on a receptor binding site. We approach the problem using a conditional variational autoencoder trained on an atomic density grid representation of cross-docked protein-ligand structures. We apply atom fitting and bond inference procedures to construct valid molecular conformations from generated atomic densities. We evaluate the properties of the generated molecules and demonstrate that they change significantly when conditioned on mutated receptors. We also explore the latent space learned by our generative model using sampling and interpolation techniques. This work opens the door for end-to-end prediction of stable bioactive molecules from protein structures with deep learning.

Adversarial Consistency for Single Domain Generalization in Medical Image Segmentation.

An organ segmentation method that can generalize to unseen contrasts and scanner settings can significantly reduce the need for retraining of deep learning models. Domain Generalization (DG) aims to achieve this goal. However, most DG methods for segmentation require training data from multiple domains during training. We propose a novel adversarial domain generalization method for organ segmentation trained on data from a single domain. We synthesize the new domains via learning an adversarial domain synthesizer (ADS) and presume that the synthetic domains cover a large enough area of plausible distributions so that unseen domains can be interpolated from synthetic domains. We propose a mutual information regularizer to enforce the semantic consistency between images from the synthetic domains, which can be estimated by patch-level contrastive learning. We evaluate our method for various organ segmentation for unseen modalities, scanning protocols, and scanner sites.

GNINA 1.0: molecular docking with deep learning.

Molecular docking computationally predicts the conformation of a small molecule when binding to a receptor. Scoring functions are a vital piece of any molecular docking pipeline as they determine the fitness of sampled poses. Here we describe and evaluate the 1.0 release of the Gnina docking software, which utilizes an ensemble of convolutional neural networks (CNNs) as a scoring function. We also explore an array of parameter values for Gnina 1.0 to optimize docking performance and computational cost. Docking performance, as evaluated by the percentage of targets where the top pose is better than 2Å root mean square deviation (Top1), is compared to AutoDock Vina scoring when utilizing explicitly defined binding pockets or whole protein docking. GNINA, utilizing a CNN scoring function to rescore the output poses, outperforms AutoDock Vina scoring on redocking and cross-docking tasks when the binding pocket is defined (Top1 increases from 58% to 73% and from 27% to 37%, respectively) and when the whole protein defines the binding pocket (Top1 increases from 31% to 38% and from 12% to 16%, respectively). The derived ensemble of CNNs generalizes to unseen proteins and ligands and produces scores that correlate well with the root mean square deviation to the known binding pose. We provide the 1.0 version of GNINA under an open source license for use as a molecular docking tool at https://github.com/gnina/gnina .

Visualizing convolutional neural network protein-ligand scoring.

Protein-ligand scoring is an important step in a structure-based drug design pipeline. Selecting a correct binding pose and predicting the binding affinity of a protein-ligand complex enables effective virtual screening. Machine learning techniques can make use of the increasing amounts of structural data that are becoming publicly available. Convolutional neural network (CNN) scoring functions in particular have shown promise in pose selection and affinity prediction for protein-ligand complexes. Neural networks are known for being difficult to interpret. Understanding the decisions of a particular network can help tune parameters and training data to maximize performance. Visualization of neural networks helps decompose complex scoring functions into pictures that are more easily parsed by humans. Here we present three methods for visualizing how individual protein-ligand complexes are interpreted by 3D convolutional neural networks. We also present a visualization of the convolutional filters and their weights. We describe how the intuition provided by these visualizations aids in network design.