Utilizing Low-Dimensional Molecular Embeddings for Rapid Chemical Similarity Search.

Nearest neighbor-based similarity searching is a common task in chemistry, with notable use cases in drug discovery. Yet, some of the most commonly used approaches for this task still leverage a brute-force approach. In practice this can be computationally costly and overly time-consuming, due in part to the sheer size of modern chemical databases. Previous computational advancements for this task have generally relied on improvements to hardware or dataset-specific tricks that lack generalizability. Approaches that leverage lower-complexity searching algorithms remain relatively underexplored. However, many of these algorithms are approximate solutions and/or struggle with typical high-dimensional chemical embeddings. Here we evaluate whether a combination of low-dimensional chemical embeddings and a k-d tree data structure can achieve fast nearest neighbor queries while maintaining performance on standard chemical similarity search benchmarks. We examine different dimensionality reductions of standard chemical embeddings as well as a learned, structurally-aware embedding-SmallSA-for this task. With this framework, searches on over one billion chemicals execute in less than a second on a single CPU core, five orders of magnitude faster than the brute-force approach. We also demonstrate that SmallSA achieves competitive performance on chemical similarity benchmarks.

HIt Discovery using docking ENriched by GEnerative Modeling (HIDDEN GEM): A novel computational workflow for accelerated virtual screening of ultra-large chemical libraries.

Recent rapid expansion of make-on-demand, purchasable, chemical libraries comprising dozens of billions or even trillions of molecules has challenged the efficient application of traditional structure-based virtual screening methods that rely on molecular docking. We present a novel computational methodology termed HIDDEN GEM (HIt Discovery using Docking ENriched by GEnerative Modeling) that greatly accelerates virtual screening. This workflow uniquely integrates machine learning, generative chemistry, massive chemical similarity searching and molecular docking of small, selected libraries in the beginning and the end of the workflow. For each target, HIDDEN GEM nominates a small number of top-scoring virtual hits prioritized from ultra-large chemical libraries. We have benchmarked HIDDEN GEM by conducting virtual screening campaigns for 16 diverse protein targets using Enamine REAL Space library comprising 37 billion molecules. We show that HIDDEN GEM yields the highest enrichment factors as compared to state of the art accelerated virtual screening methods, while requiring the least computational resources. HIDDEN GEM can be executed with any docking software and employed by users with limited computational resources.

Constraining de Sitter Space in String Theory.

We argue that the heterotic string does not have classical vacua corresponding to de Sitter space-times of dimension four or higher. The same conclusion applies to type II vacua in the absence of Ramond-Ramond fluxes. Our argument extends prior supergravity no-go results to regimes of high curvature. We discuss the interpretation of the heterotic result from the perspective of dual type II orientifold constructions. Our result suggests that the genericity arguments used in string landscape discussions should be viewed with caution.