Marcelo Der Torossian Torres

Natalie Maus, Yimeng Zeng, Haydn Thomas Jones et al.

Many key challenges in biological design-such as small-molecule drug discovery, antimicrobial peptide development, and protein engineering-can be framed as black-box optimization over vast, complex structured spaces. Existing methods rely mainly on raw structural data and struggle to exploit the rich scientific literature. While large language models (LLMs) have been added to these pipelines, they have been confined to narrow roles within structure-centered optimizers. We instead cast biological black-box optimization as a fully agentic, language-based reasoning process. We introduce Purely Agentic BLack-box Optimization (PABLO), a hierarchical agentic system that uses scientific LLMs pretrained on chemistry and biology literature to generate and iteratively refine biological candidates. On both the standard GuacaMol molecular design and antimicrobial peptide optimization tasks, PABLO achieves state-of-the-art performance, substantially improving sample efficiency and final objective values over established baselines. Compared to prior optimization methods that incorporate LLMs, PABLO achieves competitive token usage per run despite relying on LLMs throughout the optimization loop. Beyond raw performance, the agentic formulation offers key advantages for realistic design: it naturally incorporates semantic task descriptions, retrieval-augmented domain knowledge, and complex constraints. In follow-up in vitro validation, PABLO-optimized peptides showed strong activity against drug-resistant pathogens, underscoring the practical potential of PABLO for therapeutic discovery.

Haydn Thomas Jones, Natalie Maus, Josh Magnus Ludan et al.

AI-driven discovery can greatly reduce design time and enhance new therapeutics' effectiveness. Models using simulators explore broad design spaces but risk violating implicit constraints due to a lack of experimental priors. For example, in a new analysis we performed on a diverse set of models on the GuacaMol benchmark using supervised classifiers, over 60\% of molecules proposed had high probability of being mutagenic. In this work, we introduce Medex, a dataset of priors for design problems extracted from literature describing compounds used in lab settings. It is constructed with LLM pipelines for discovering therapeutic entities in relevant paragraphs and summarizing information in concise fair-use facts. Medex consists of 32.3 million pairs of natural language facts, and appropriate entity representations (i.e. SMILES or refseq IDs). To demonstrate the potential of the data, we train LLM, CLIP, and LLava architectures to reason jointly about text and design targets and evaluate on tasks from the Therapeutic Data Commons (TDC). Medex is highly effective for creating models with strong priors: in supervised prediction problems that use our data as pretraining, our best models with 15M learnable parameters outperform larger 2B TxGemma on both regression and classification TDC tasks, and perform comparably to 9B models on average. Models built with Medex can be used as constraints while optimizing for novel molecules in GuacaMol, resulting in proposals that are safer and nearly as effective. We release our dataset at https://huggingface.co/datasets/medexanon/Medex, and will provide expanded versions as available literature grows.

Natalie Maus, Kyurae Kim, Yimeng Zeng et al.

In multi-objective black-box optimization, the goal is typically to find solutions that optimize a set of $T$ black-box objective functions, $f_1, \ldots f_T$, simultaneously. Traditional approaches often seek a single Pareto-optimal set that balances trade-offs among all objectives. In contrast, we consider a problem setting that departs from this paradigm: finding a small set of $K < T$ solutions, that collectively "cover" the $T$ objectives. A set of solutions is defined as "covering" if, for each objective $f_1, \ldots f_T$, there is at least one good solution. A motivating example for this problem setting occurs in drug design. For example, we may have $T$ pathogens and aim to identify a set of $K < T$ antibiotics such that at least one antibiotic can be used to treat each pathogen. This problem, known as coverage optimization, has yet to be tackled with the Bayesian optimization (BO) framework. To fill this void, we develop Multi-Objective Coverage Bayesian Optimization (MOCOBO), a BO algorithm for solving coverage optimization. Our approach is based on a new acquisition function reminiscent of expected improvement in the vanilla BO setup. We demonstrate the performance of our method on high-dimensional black-box optimization tasks, including applications in peptide and molecular design. Results show that the coverage of the $K < T$ solutions found by MOCOBO matches or nearly matches the coverage of $T$ solutions obtained by optimizing each objective individually. Furthermore, in in vitro experiments, the peptides found by MOCOBO exhibited high potency against drug-resistant pathogens, further demonstrating the potential of MOCOBO for drug discovery. All of our code is publicly available at the following link: https://github.com/nataliemaus/mocobo.

Tianang Leng, Fangping Wan, Marcelo Der Torossian Torres et al.

Antimicrobial resistance (AMR) is escalating and outpacing current antibiotic development. Thus, discovering antibiotics effective against emerging pathogens is becoming increasingly critical. However, existing approaches cannot rapidly identify effective molecules against novel pathogens or emerging drug-resistant strains. Here, we introduce ApexOracle, an artificial intelligence (AI) model that both predicts the antibacterial potency of existing compounds and designs de novo molecules active against strains it has never encountered. Departing from models that rely solely on molecular features, ApexOracle incorporates pathogen-specific context through the integration of molecular features captured via a foundational discrete diffusion language model and a dual-embedding framework that combines genomic- and literature-derived strain representations. Across diverse bacterial species and chemical modalities, ApexOracle consistently outperformed state-of-the-art approaches in activity prediction and demonstrated reliable transferability to novel pathogens with little or no antimicrobial data. Its unified representation-generation architecture further enables the in silico creation of "new-to-nature" molecules with high predicted efficacy against priority threats. By pairing rapid activity prediction with targeted molecular generation, ApexOracle offers a scalable strategy for countering AMR and preparing for future infectious-disease outbreaks.

Diogo Soares, Leon Hetzel, Paulina Szymczak et al.

Deep learning-based antimicrobial peptide (AMP) discovery faces critical challenges such as limited controllability, lack of representations that efficiently model antimicrobial properties, and low experimental hit rates. To address these challenges, we introduce OmegAMP, a framework designed for reliable AMP generation with increased controllability. Its diffusion-based generative model leverages a novel conditioning mechanism to achieve fine-grained control over desired physicochemical properties and to direct generation towards specific activity profiles, including species-specific effectiveness. This is further enhanced by a biologically informed encoding space that significantly improves overall generative performance. Complementing these generative capabilities, OmegAMP leverages a novel synthetic data augmentation strategy to train classifiers for AMP filtering, drastically reducing false positive rates and thereby increasing the likelihood of experimental success. Our in silico experiments demonstrate that OmegAMP delivers state-of-the-art performance across key stages of the AMP discovery pipeline, enabling us to achieve an unprecedented success rate in wet lab experiments. We tested 25 candidate peptides, 24 of them (96%) demonstrated antimicrobial activity, proving effective even against multi-drug resistant strains. Our findings underscore OmegAMP's potential to significantly advance computational frameworks in the fight against antimicrobial resistance.

Marcin Możejko, Adam Bielecki, Jurand Prądzyński et al.

Antimicrobial peptide discovery is challenged by the astronomical size of peptide space and the relative scarcity of active peptides. Generative models provide continuous latent "maps" of peptide space, but conventionally ignore decoder-induced geometry and rely on flat Euclidean metrics, rendering exploration and optimization distorted and inefficient. Prior manifold-based remedies assume fixed intrinsic dimensionality, which critically fails in practice for peptide data. Here, we introduce PepCompass, a geometry-aware framework for peptide exploration and optimization. At its core, we define a Union of $κ$-Stable Riemannian Manifolds $\mathbb{M}^κ$, a family of decoder-induced manifolds that captures local geometry while ensuring computational stability. We propose two local exploration methods: Second-Order Riemannian Brownian Efficient Sampling, which provides a convergent second-order approximation to Riemannian Brownian motion, and Mutation Enumeration in Tangent Space, which reinterprets tangent directions as discrete amino-acid substitutions. Combining these yields Local Enumeration Bayesian Optimization (LE-BO), an efficient algorithm for local activity optimization. Finally, we introduce Potential-minimizing Geodesic Search (PoGS), which interpolates between prototype embeddings along property-enriched geodesics, biasing discovery toward seeds, i.e. peptides with favorable activity. In-vitro validation confirms the effectiveness of PepCompass: PoGS yields four novel seeds, and subsequent optimization with LE-BO discovers 25 highly active peptides with broad-spectrum activity, including against resistant bacterial strains. These results demonstrate that geometry-informed exploration provides a powerful new paradigm for antimicrobial peptide design.

Yimeng Zeng, Natalie Maus, Haydn Thomas Jones et al.

In multi-task Bayesian optimization, the goal is to leverage experience from optimizing existing tasks to improve the efficiency of optimizing new ones. While approaches using multi-task Gaussian processes or deep kernel transfer exist, the performance improvement is marginal when scaling beyond a moderate number of tasks. We introduce a novel approach leveraging large language models (LLMs) to learn from, and improve upon, previous optimization trajectories, scaling to approximately 1500 distinct tasks. Specifically, we propose a feedback loop in which an LLM is fine-tuned on the high quality solutions to specific tasks found by Bayesian optimization (BO). This LLM is then used to generate initialization points for future BO searches for new tasks. The trajectories of these new searches provide additional training data for fine-tuning the LLM, completing the loop. We evaluate our method on two distinct domains: database query optimization and antimicrobial peptide design. Results demonstrate that our approach creates a positive feedback loop, where the LLM's generated initializations gradually improve, leading to better optimization performance. As this feedback loop continues, we find that the LLM is eventually able to generate solutions to new tasks in just a few shots that are better than the solutions produced by "from scratch" by Bayesian optimization while simultaneously requiring significantly fewer oracle calls.