Generative Active Learning for the Search of Small-molecule Protein Binders

Despite substantial progress in machine learning for scientific discovery in recent years, truly de novo design of small molecules which exhibit a property of interest remains a significant challenge. We introduce LambdaZero, a generative active learning approach to search for synthesizable molecules. Powered by deep reinforcement learning, LambdaZero learns to search over the vast space of molecules to discover candidates with a desired property. We apply LambdaZero with molecular docking to design novel small molecules that inhibit the enzyme soluble Epoxide Hydrolase 2 (sEH), while enforcing constraints on synthesizability and drug-likeliness. LambdaZero provides an exponential speedup in terms of the number of calls to the expensive molecular docking oracle, and LambdaZero de novo designed molecules reach docking scores that would otherwise require the virtual screening of a hundred billion molecules. Importantly, LambdaZero discovers novel scaffolds of synthesizable, drug-like inhibitors for sEH. In in vitro experimental validation, a series of ligands from a generated quinazoline-based scaffold were synthesized, and the lead inhibitor N-(4,6-di(pyrrolidin-1-yl)quinazolin-2-yl)-N-methylbenzamide (UM0152893) displayed sub-micromolar enzyme inhibition of sEH.

A Generative Model of Symmetry Transformations

Correctly capturing the symmetry transformations of data can lead to efficient models with strong generalization capabilities, though methods incorporating symmetries often require prior knowledge. While recent advancements have been made in learning those symmetries directly from the dataset, most of this work has focused on the discriminative setting. In this paper, we construct a generative model that explicitly aims to capture symmetries in the data, resulting in a model that learns which symmetries are present in an interpretable way. We provide a simple algorithm for efficiently learning our generative model and demonstrate its ability to capture symmetries under affine and color transformations. Combining our symmetry model with existing generative models results in higher marginal test-log-likelihoods and robustness to data sparsification.

Diffusive Gibbs Sampling

The inadequate mixing of conventional Markov Chain Monte Carlo (MCMC) methods for multi-modal distributions presents a significant challenge in practical applications such as Bayesian inference and molecular dynamics. Addressing this, we propose Diffusive Gibbs Sampling (DiGS), an innovative family of sampling methods designed for effective sampling from distributions characterized by distant and disconnected modes. DiGS integrates recent developments in diffusion models, leveraging Gaussian convolution to create an auxiliary noisy distribution that bridges isolated modes in the original space and applying Gibbs sampling to alternately draw samples from both spaces. Our approach exhibits a better mixing property for sampling multi-modal distributions than state-of-the-art methods such as parallel tempering. We demonstrate that our sampler attains substantially improved results across various tasks, including mixtures of Gaussians, Bayesian neural networks and molecular dynamics.

Stochastic Gradient Descent for Gaussian Processes Done Right

We study the optimisation problem associated with Gaussian process regression using squared loss. The most common approach to this problem is to apply an exact solver, such as conjugate gradient descent, either directly, or to a reduced-order version of the problem. Recently, driven by successes in deep learning, stochastic gradient descent has gained traction as an alternative. In this paper, we show that when done right$\unicode{x2014}$by which we mean using specific insights from the optimisation and kernel communities$\unicode{x2014}$this approach is highly effective. We thus introduce a particular stochastic dual gradient descent algorithm, that may be implemented with a few lines of code using any deep learning framework. We explain our design decisions by illustrating their advantage against alternatives with ablation studies and show that the new method is highly competitive. Our evaluations on standard regression benchmarks and a Bayesian optimisation task set our approach apart from preconditioned conjugate gradients, variational Gaussian process approximations, and a previous version of stochastic gradient descent for Gaussian processes. On a molecular binding affinity prediction task, our method places Gaussian process regression on par in terms of performance with state-of-the-art graph neural networks.

Introducing instance label correlation in multiple instance learning. Application to cancer detection on histopathological images

In the last years, the weakly supervised paradigm of multiple instance learning (MIL) has become very popular in many different areas. A paradigmatic example is computational pathology, where the lack of patch-level labels for whole-slide images prevents the application of supervised models. Probabilistic MIL methods based on Gaussian Processes (GPs) have obtained promising results due to their excellent uncertainty estimation capabilities. However, these are general-purpose MIL methods that do not take into account one important fact: in (histopathological) images, the labels of neighboring patches are expected to be correlated. In this work, we extend a state-of-the-art GP-based MIL method, which is called VGPMIL-PR, to exploit such correlation. To do so, we develop a novel coupling term inspired by the statistical physics Ising model. We use variational inference to estimate all the model parameters. Interestingly, the VGPMIL-PR formulation is recovered when the weight that regulates the strength of the Ising term vanishes. The performance of the proposed method is assessed in two real-world problems of prostate cancer detection. We show that our model achieves better results than other state-of-the-art probabilistic MIL methods. We also provide different visualizations and analysis to gain insights into the influence of the novel Ising term. These insights are expected to facilitate the application of the proposed model to other research areas.

Series of Hessian-Vector Products for Tractable Saddle-Free Newton Optimisation of Neural Networks

Despite their popularity in the field of continuous optimisation, second-order quasi-Newton methods are challenging to apply in machine learning, as the Hessian matrix is intractably large. This computational burden is exacerbated by the need to address non-convexity, for instance by modifying the Hessian's eigenvalues as in Saddle-Free Newton methods. We propose an optimisation algorithm which addresses both of these concerns - to our knowledge, the first efficiently-scalable optimisation algorithm to asymptotically use the exact (eigenvalue-modified) inverse Hessian. Our method frames the problem as a series which principally square-roots and inverts the squared Hessian, then uses it to precondition a gradient vector, all without explicitly computing or eigendecomposing the Hessian. A truncation of this infinite series provides a new optimisation algorithm which is scalable and comparable to other first- and second-order optimisation methods in both runtime and optimisation performance. We demonstrate this in a variety of settings, including a ResNet-18 trained on CIFAR-10.

Adam through a Second-Order Lens

Research into optimisation for deep learning is characterised by a tension between the computational efficiency of first-order, gradient-based methods (such as SGD and Adam) and the theoretical efficiency of second-order, curvature-based methods (such as quasi-Newton methods and K-FAC). We seek to combine the benefits of both approaches into a single computationally-efficient algorithm. Noting that second-order methods often depend on stabilising heuristics (such as Levenberg-Marquardt damping), we propose AdamQLR: an optimiser combining damping and learning rate selection techniques from K-FAC (Martens and Grosse, 2015) with the update directions proposed by Adam, inspired by considering Adam through a second-order lens. We evaluate AdamQLR on a range of regression and classification tasks at various scales, achieving competitive generalisation performance vs runtime.

Retro-fallback: retrosynthetic planning in an uncertain world

Retrosynthesis is the task of proposing a series of chemical reactions to create a desired molecule from simpler, buyable molecules. While previous works have proposed algorithms to find optimal solutions for a range of metrics (e.g. shortest, lowest-cost), these works generally overlook the fact that we have imperfect knowledge of the space of possible reactions, meaning plans created by the algorithm may not work in a laboratory. In this paper we propose a novel formulation of retrosynthesis in terms of stochastic processes to account for this uncertainty. We then propose a novel greedy algorithm called retro-fallback which maximizes the probability that at least one synthesis plan can be executed in the lab. Using in-silico benchmarks we demonstrate that retro-fallback generally produces better sets of synthesis plans than the popular MCTS and retro* algorithms.

Genetic algorithms are strong baselines for molecule generation

Generating molecules, both in a directed and undirected fashion, is a huge part of the drug discovery pipeline. Genetic algorithms (GAs) generate molecules by randomly modifying known molecules. In this paper we show that GAs are very strong algorithms for such tasks, outperforming many complicated machine learning methods: a result which many researchers may find surprising. We therefore propose insisting during peer review that new algorithms must have some clear advantage over GAs, which we call the GA criterion. Ultimately our work suggests that a lot of research in molecule generation should be re-assessed.

RECOMBINER: Robust and Enhanced Compression with Bayesian Implicit Neural Representations

COMpression with Bayesian Implicit NEural Representations (COMBINER) is a recent data compression method that addresses a key inefficiency of previous Implicit Neural Representation (INR)-based approaches: it avoids quantization and enables direct optimization of the rate-distortion performance. However, COMBINER still has significant limitations: 1) it uses factorized priors and posterior approximations that lack flexibility; 2) it cannot effectively adapt to local deviations from global patterns in the data; and 3) its performance can be susceptible to modeling choices and the variational parameters' initializations. Our proposed method, Robust and Enhanced COMBINER (RECOMBINER), addresses these issues by 1) enriching the variational approximation while maintaining its computational cost via a linear reparameterization of the INR weights, 2) augmenting our INRs with learnable positional encodings that enable them to adapt to local details and 3) splitting high-resolution data into patches to increase robustness and utilizing expressive hierarchical priors to capture dependency across patches. We conduct extensive experiments across several data modalities, showcasing that RECOMBINER achieves competitive results with the best INR-based methods and even outperforms autoencoder-based codecs on low-resolution images at low bitrates.