Alexander Tropsha

Pavel Koptev, Nikita Krainov, Konstantin Malkov et al.

Machine learning models of chemical bioactivity are increasingly used for prioritizing a small number of compounds in virtual screening libraries for experimental follow-up. In these applications, assessing model accuracy by early hit enrichment such as Positive Predicted Value (PPV) calculated for top N hits (PPV@N) is more appropriate and actionable than traditional global metrics such as AUC. We present KANEL, an ensemble workflow that combines interpretable Kolmogorov-Arnold Networks (KANs) with XGBoost, random forest, and multilayer perceptron models trained on complementary molecular representations (LillyMol descriptors, RDKit-derived descriptors, and Morgan fingerprints).

Kathryn E. Kirchoff, Travis Maxfield, Alexander Tropsha et al.

In deep learning for drug discovery, chemical data are often represented as simplified molecular-input line-entry system (SMILES) sequences which allow for straightforward implementation of natural language processing methodologies, one being the sequence-to-sequence autoencoder. However, we observe that training an autoencoder solely on SMILES is insufficient to learn molecular representations that are semantically meaningful, where semantics are defined by the structural (graph-to-graph) similarities between molecules. We demonstrate by example that autoencoders may map structurally similar molecules to distant codes, resulting in an incoherent latent space that does not respect the structural similarities between molecules. To address this shortcoming we propose Semantically-Aware Latent Space Autoencoder (SALSA), a transformer-autoencoder modified with a contrastive task, tailored specifically to learn graph-to-graph similarity between molecules. Formally, the contrastive objective is to map structurally similar molecules (separated by a single graph edit) to nearby codes in the latent space. To accomplish this, we generate a novel dataset comprised of sets of structurally similar molecules and opt for a supervised contrastive loss that is able to incorporate full sets of positive samples. We compare SALSA to its ablated counterparts, and show empirically that the composed training objective (reconstruction and contrastive task) leads to a higher quality latent space that is more 1) structurally-aware, 2) semantically continuous, and 3) property-aware.

Kathryn E. Kirchoff, James Wellnitz, Joshua E. Hochuli et al.

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.

Rishabh Dey, Michael Brocidiacono, Kushal Koirala et al.

The implicit solvent approach offers a computationally efficient framework to model solvation effects in molecular simulations. However, its accuracy often falls short compared to explicit solvent models, limiting its use in precise thermodynamic calculations. Recent advancements in machine learning (ML) present an opportunity to overcome these limitations by leveraging neural networks to develop more precise implicit solvent potentials for diverse applications. A major drawback of current ML-based methods is their reliance on force-matching alone, which can lead to energy predictions that differ by an arbitrary constant and are therefore unsuitable for absolute free energy comparisons. Here, we introduce a novel methodology with a graph neural network (GNN)-based implicit solvent model, dubbed Lambda Solvation Neural Network (LSNN). In addition to force-matching, this network was trained to match the derivatives of alchemical variables, ensuring that solvation free energies can be meaningfully compared across chemical species.. Trained on a dataset of approximately 300,000 small molecules, LSNN achieves free energy predictions with accuracy comparable to explicit-solvent alchemical simulations, while offering a computational speedup and establishing a foundational framework for future applications in drug discovery.

Yunni Qu, James Wellnitz, Dzung Dinh et al.

EXPLOR is a novel framework that utilizes support-expanding, extrapolatory pseudo-labeling to improve prediction and uncertainty-based rejection on out-of-distribution (OOD) points. EXPLOR utilizes a diverse set of base models as pseudo-labelers on the expansive augmented data to improve OOD performance through multiple MLP heads (one per base model) with shared embedding trained with a novel per-head matching loss. Unlike prior methods that rely on modality-specific augmentations or assume access to OOD data, EXPLOR introduces extrapolatory pseudo-labeling on latent-space augmentations, enabling robust OOD generalization with any real-valued vector data. In contrast to prior modality-agnostic methods with neural backbones, EXPLOR is model-agnostic, working effectively with methods from simple tree-based models to complex OOD generalization models. We demonstrate that EXPLOR achieves superior performance compared to state-of-the-art methods on diverse datasets in single-source domain generalization settings.

Rahul Yedida, Saad Mohammad Abrar, Cleber Melo-Filho et al.

Objective: We aim to learn potential novel cures for diseases from unstructured text sources. More specifically, we seek to extract drug-disease pairs of potential cures to diseases by a simple reasoning over the structure of spoken text. Materials and Methods: We use Google Cloud to transcribe podcast episodes of an NPR radio show. We then build a pipeline for systematically pre-processing the text to ensure quality input to the core classification model, which feeds to a series of post-processing steps for obtaining filtered results. Our classification model itself uses a language model pre-trained on PubMed text. The modular nature of our pipeline allows for ease of future developments in this area by substituting higher quality components at each stage of the pipeline. As a validation measure, we use ROBOKOP, an engine over a medical knowledge graph with only validated pathways, as a ground truth source for checking the existence of the proposed pairs. For the proposed pairs not found in ROBOKOP, we provide further verification using Chemotext. Results: We found 30.4% of our proposed pairs in the ROBOKOP database. For example, our model successfully identified that Omeprazole can help treat heartburn.We discuss the significance of this result, showing some examples of the proposed pairs. Discussion and Conclusion: The agreement of our results with the existing knowledge source indicates a step in the right direction. Given the plug-and-play nature of our framework, it is easy to add, remove, or modify parts to improve the model as necessary. We discuss the results showing some examples, and note that this is a potentially new line of research that has further scope to be explored. Although our approach was originally oriented on radio podcast transcripts, it is input-agnostic and could be applied to any source of textual data and to any problem of interest.

Mariya Popova, Olexandr Isayev, Alexander Tropsha

We propose a novel computational strategy for de novo design of molecules with desired properties termed ReLeaSE (Reinforcement Learning for Structural Evolution). Based on deep and reinforcement learning approaches, ReLeaSE integrates two deep neural networks - generative and predictive - that are trained separately but employed jointly to generate novel targeted chemical libraries. ReLeaSE employs simple representation of molecules by their SMILES strings only. Generative models are trained with stack-augmented memory network to produce chemically feasible SMILES strings, and predictive models are derived to forecast the desired properties of the de novo generated compounds. In the first phase of the method, generative and predictive models are trained separately with a supervised learning algorithm. In the second phase, both models are trained jointly with the reinforcement learning approach to bias the generation of new chemical structures towards those with the desired physical and/or biological properties. In the proof-of-concept study, we have employed the ReLeaSE method to design chemical libraries with a bias toward structural complexity or biased toward compounds with either maximal, minimal, or specific range of physical properties such as melting point or hydrophobicity, as well as to develop novel putative inhibitors of JAK2. The approach proposed herein can find a general use for generating targeted chemical libraries of novel compounds optimized for either a single desired property or multiple properties.