Active Learning-Guided Seq2Seq Variational Autoencoder for Multi-target Inhibitor Generation

Simultaneously optimizing molecules against multiple therapeutic targets remains a profound challenge in drug discovery, particularly due to sparse rewards and conflicting design constraints. We propose a structured active learning (AL) paradigm integrating a sequence-to-sequence (Seq2Seq) variational autoencoder (VAE) into iterative loops designed to balance chemical diversity, molecular quality, and multi-target affinity. Our method alternates between expanding chemically feasible regions of latent space and progressively constraining molecules based on increasingly stringent multi-target docking thresholds. In a proof-of-concept study targeting three related coronavirus main proteases (SARS-CoV-2, SARS-CoV, MERS-CoV), our approach efficiently generated a structurally diverse set of pan-inhibitor candidates. We demonstrate that careful timing and strategic placement of chemical filters within this active learning pipeline markedly enhance exploration of beneficial chemical space, transforming the sparse-reward, multi-objective drug design problem into an accessible computational task. Our framework thus provides a generalizable roadmap for efficiently navigating complex polypharmacological landscapes.

ICML Topological Deep Learning Challenge 2024: Beyond the Graph Domain

This paper describes the 2nd edition of the ICML Topological Deep Learning Challenge that was hosted within the ICML 2024 ELLIS Workshop on Geometry-grounded Representation Learning and Generative Modeling (GRaM). The challenge focused on the problem of representing data in different discrete topological domains in order to bridge the gap between Topological Deep Learning (TDL) and other types of structured datasets (e.g. point clouds, graphs). Specifically, participants were asked to design and implement topological liftings, i.e. mappings between different data structures and topological domains --like hypergraphs, or simplicial/cell/combinatorial complexes. The challenge received 52 submissions satisfying all the requirements. This paper introduces the main scope of the challenge, and summarizes the main results and findings.

Scoreformer: A Surrogate Model For Large-Scale Prediction of Docking Scores

In this study, we present ScoreFormer, a novel graph transformer model designed to accurately predict molecular docking scores, thereby optimizing high-throughput virtual screening (HTVS) in drug discovery. The architecture integrates Principal Neighborhood Aggregation (PNA) and Learnable Random Walk Positional Encodings (LRWPE), enhancing the model's ability to understand complex molecular structures and their relationship with their respective docking scores. This approach significantly surpasses traditional HTVS methods and recent Graph Neural Network (GNN) models in both recovery and efficiency due to a wider coverage of the chemical space and enhanced performance. Our results demonstrate that ScoreFormer achieves competitive performance in docking score prediction and offers a substantial 1.65-fold reduction in inference time compared to existing models. We evaluated ScoreFormer across multiple datasets under various conditions, confirming its robustness and reliability in identifying potential drug candidates rapidly.

Optimizing Drug Design by Merging Generative AI With Active Learning Frameworks

Traditional drug discovery programs are being transformed by the advent of machine learning methods. Among these, Generative AI methods (GM) have gained attention due to their ability to design new molecules and enhance specific properties of existing ones. However, current GM methods have limitations, such as low affinity towards the target, unknown ADME/PK properties, or the lack of synthetic tractability. To improve the applicability domain of GM methods, we have developed a workflow based on a variational autoencoder coupled with active learning steps. The designed GM workflow iteratively learns from molecular metrics, including drug likeliness, synthesizability, similarity, and docking scores. In addition, we also included a hierarchical set of criteria based on advanced molecular modeling simulations during a final selection step. We tested our GM workflow on two model systems, CDK2 and KRAS. In both cases, our model generated chemically viable molecules with a high predicted affinity toward the targets. Particularly, the proportion of high-affinity molecules inferred by our GM workflow was significantly greater than that in the training data. Notably, we also uncovered novel scaffolds significantly dissimilar to those known for each target. These results highlight the potential of our GM workflow to explore novel chemical space for specific targets, thereby opening up new possibilities for drug discovery endeavors.