Compositional Deep Probabilistic Models of DNA-Encoded Libraries

• Published in: Journal of chemical information and modeling Vol. 64; no. 4; pp. 1123 - 1133
• Main Authors: Chen, Benson, Sultan, Mohammad M., Karaletsos, Theofanis
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 26-02-2024
• Subjects: Complexity; Deoxyribonucleic acid; DNA; Gene sequencing; Machine learning; Machine Learning and Deep Learning; Molecular structure; Probabilistic models; Software
• ISSN: 1549-9596; 1549-960X; 1549-960X
• DOI: 10.1021/acs.jcim.3c01699

DNA-encoded library (DEL) has proven to be a powerful tool that utilizes combinatorially constructed small molecules to facilitate highly efficient screening experiments. These selection experiments, involving multiple stages of washing, elution, and identification of potent binders via unique DNA barcodes, often generate complex data. This complexity can potentially mask the underlying signals, necessitating the application of computational tools, such as machine learning, to uncover valuable insights. We introduce a compositional deep probabilistic model of DEL data, DEL-Compose, which decomposes molecular representations into their monosynthon, disynthon, and trisynthon building blocks and capitalizes on the inherent hierarchical structure of these molecules by modeling latent reactions between embedded synthons. Additionally, we investigate methods to improve the observation models for DEL count data, such as integrating covariate factors to more effectively account for data noise. Across two popular public benchmark data sets (CA-IX and HRP), our model demonstrates strong performance compared to count baselines, enriches the correct pharmacophores, and offers valuable insights via its intrinsic interpretable structure, thereby providing a robust tool for the analysis of DEL data.