James Wellnitz , Brandon Novy , Shu-Hang Lin , Travis Maxfield , Matthew Axtman , Tina M. Leisner , Eric M. Merten , Ivanna Zhilinskaya , Devan J. Shell , Kellyn M. Schroeder , Jacqueline L. Norris-Drouin , P. Brian Hardy , Kenneth H. Pearce , Konstantin I. Popov

Journal of Cheminformatics

DOI: 10.1186/s13321-026-01296-1

Abstract

DNA-encoded library (DEL) technology has become a powerful tool in modern drug discovery. However, fully harnessing its potential requires the use of extensive computational methods, which are often available only through proprietary software. This restricts accessibility for small teams lacking robust informatics support, hindering the growth of the technology. Objective We introduce DELi, an open-source DEL informatics platform developed for library design, next-generation sequencing (NGS) read processing, and binding data analysis. Implementation DELi offers a simple and flexible configuration setup that is readily customizable, while remaining easy to use and supported by a clear user interface. To showcase its capabilities, we used DELi to design a custom benzimidazole-based DEL (UNCDEL006), and performed proof-of-concept selection experiments against bromodomain-containing protein 4 (BRD4). Results The DELi decoding and analysis modules identified top-performing compounds, leading to the off-DNA synthesis of UNC11951. This compound was confirmed as a nanomolar BRD4 binder via isothermal titration calorimetry (ITC) and demonstrated thermal shift stabilization as observed by differential scanning fluorimetry (DSF). These results demonstrate DELi as an effective tool for DEL design and analysis. Availability DELi is written in Python and made available through PyPi and GitHub, alongside the open-sourced UNCDEL006 library. Scientific contribution DELi addresses the need for accessible computational tools for DEL by integrating robust analysis methods within a cohesive, open-source platform. It provides a fully documented and experimentally validated end-to-end workflow, improving reproducibility and lowering the barrier to entry for researchers adopting DEL technology.