Organic Chemistry

A Machine-learning-based Data Analysis Method for Cell-based Selection of DNA-encoded libraries (DELs)

Authors

  • Rui Hou University of Hong Kong & Laboratory for Synthetic Chemistry and Chemical Biology Limited, [email protected] ,
  • Chao Xie University of Hong Kong ,
  • Yuhan Gui University of Hong Kong & State Key Laboratory of Synthetic Chemistry ,
  • Gang Li Shenzhen Bay Laboratory ,
  • Xiaoyu Li University of Hong Kong & Laboratory for Synthetic Chemistry and Chemical Biology Limited, [email protected] & State Key Laboratory of Synthetic Chemistry

Abstract

DNA-encoded library (DEL) is a powerful ligand discovery technology that has been widely adopted in the pharmaceutical industry. DEL selections are typically performed with a purified protein target immobilized on a matrix or in solution phase. Recently, DELs have also been used to interrogate the targets in complex biological environment, such as membrane proteins on live cells. However, due to the complex landscape of the cell surface, the selection inevitably involves significant non-specific interactions, and the selection data is much noisier than the ones with purified proteins, making reliable hit identification highly challenging. Researchers have developed several approaches to denoise DEL datasets, but it remains unclear whether they are suitable for cell-based DEL selections. Here, we propose a new machine-learning (ML)-based approach to process cell-based DEL selection datasets by using a Maximum A Posteriori (MAP) estimation loss function, a probabilistic framework that can account for and quantify uncertainties of noisy data. We applied the approach to a DEL selection dataset, where a library of 7,721,415 compounds was selected against a purified carbonic anhydrase 2 (CA-2) and a cell line expressing the membrane protein carbonic anhydrase 12 (CA-12). The Extended-Connectivity Fingerprint (ECFP)-based regression model using the MAP loss function was able to identify the true binders and also reliable structure-activity relationship (SAR) from the noisy cell-based selection datasets. In addition, the regularized enrichment metric (known as MAP enrichment) could also be calculated directly without involving the specific machine learning model, effectively suppressing low-confidence outliers and enhancing the signal-to-noise ratio.

Content

Thumbnail image of manuscript_final.pdf

Supplementary material

Thumbnail image of SI final.pdf
Supporting Information
Supplementary figures, tables, and experimental methods.