Discovery of TIGIT inhibitors based on DEL and machine learning

Feng Xiong; Mingao Yu; Honggui Xu; Zhenmin Zhong; Zhenwei Li; Yuhan Guo; Tianyuan Zhang; Zhixuan Zeng; Feng Jin; Xun He

doi:10.3389/fchem.2022.982539

Discovery of TIGIT inhibitors based on DEL and machine learning

Front Chem. 2022 Jul 26:10:982539. doi: 10.3389/fchem.2022.982539. eCollection 2022.

Authors

Feng Xiong¹, Mingao Yu², Honggui Xu², Zhenmin Zhong¹, Zhenwei Li¹, Yuhan Guo², Tianyuan Zhang², Zhixuan Zeng¹, Feng Jin², Xun He¹

Affiliations

¹ Shenzhen Innovation Center for Small Molecule Drug Discovery Co., Ltd., Shenzhen, China.
² Shenzhen NewDEL Biotech Co., Ltd., Shenzhen, China.

Abstract

Drug discovery has entered a new period of vigorous development with advanced technologies such as DNA-encoded library (DEL) and artificial intelligence (AI). The previous DEL-AI combination has been successfully applied in the drug discovery of classical kinase and receptor targets mainly based on the known scaffold. So far, there is no report of the DEL-AI combination on inhibitors targeting protein-protein interaction, including those undruggable targets with few or unknown active scaffolds. Here, we applied DEL technology on the T cell immunoglobulin and ITIM domain (TIGIT) target, resulting in the unique hit compound 1 (IC₅₀ = 20.7 μM). Based on the screening data from DEL and hit derivatives a1-a34, a machine learning (ML) modeling process was established to address the challenge of poor sample distribution uniformity, which is also frequently encountered in DEL screening on new targets. In the end, the established ML model achieved a satisfactory hit rate of about 75% for derivatives in a high-scored area.

Keywords: DNA-encoded library; TIGIT; anti-tumor; machine learning; protein-protein interaction.