Paulina Szymczak

Paulina Szymczak, Ewa Szczurek

Antimicrobial peptides (AMPs) emerge as promising agents against antimicrobial resistance, providing an alternative to conventional antibiotics. Artificial intelligence (AI) revolutionized AMP discovery through both discrimination and generation approaches. The discriminators aid the identification of promising candidates by predicting key peptide properties such as activity and toxicity, while the generators learn the distribution over peptides and enable sampling novel AMP candidates, either de novo, or as analogues of a prototype peptide. Moreover, the controlled generation of AMPs with desired properties is achieved by discriminator-guided filtering, positive-only learning, latent space sampling, as well as conditional and optimized generation. Here we review recent achievements in AI-driven AMP discovery, highlighting the most exciting directions.

Krzysztof Koras, Marcin Możejko, Paulina Szymczak et al.

Recent emergence of high-throughput drug screening assays sparkled an intensive development of machine learning methods, including models for prediction of sensitivity of cancer cell lines to anti-cancer drugs, as well as methods for generation of potential drug candidates. However, a concept of generation of compounds with specific properties and simultaneous modeling of their efficacy against cancer cell lines has not been comprehensively explored. To address this need, we present VADEERS, a Variational Autoencoder-based Drug Efficacy Estimation Recommender System. The generation of compounds is performed by a novel variational autoencoder with a semi-supervised Gaussian Mixture Model (GMM) prior. The prior defines a clustering in the latent space, where the clusters are associated with specific drug properties. In addition, VADEERS is equipped with a cell line autoencoder and a sensitivity prediction network. The model combines data for SMILES string representations of anti-cancer drugs, their inhibition profiles against a panel of protein kinases, cell lines biological features and measurements of the sensitivity of the cell lines to the drugs. The evaluated variants of VADEERS achieve a high r=0.87 Pearson correlation between true and predicted drug sensitivity estimates. We train the GMM prior in such a way that the clusters in the latent space correspond to a pre-computed clustering of the drugs by their inhibitory profiles. We show that the learned latent representations and new generated data points accurately reflect the given clustering. In summary, VADEERS offers a comprehensive model of drugs and cell lines properties and relationships between them, as well as a guided generation of novel compounds.

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.