Discovery of TYR inhibitors from de novo molecular generation to dual-track lead optimization: “Competition” between AI and chemists
- Yinyan Sun
- Jiahui Wang
- Wenchao Chen
- Xiaoying Jiang
- Shan Wang
- Jia Zhi
- Feifan Li
- Meiling Feng
- Xiaotian Niu
- Bin Ju
- Jianan Guo
- Renren Bai
2026-06-19
This study introduces a unified framework combining artificial intelligence (AI)–directed de novo molecular generation with dual-track lead optimization—comprising expert-guided strategies and AI-driven pathways—to discover tyrosinase (TYR) inhibitors for hyperpigmentation disorders. Using a reinforcement learning (RL)–based generative model, the lead compound AI10 was identified. Subsequent optimization followed two parallel routes. The expert-guided approach yielded AI10-m15 as the most potent TYR inhibitor, with notable antipigmentation activity and excellent cellular safety profiles. In contrast, the AI-driven pathway explored broader chemical spaces, generating unconventional chemotypes, exemplified by the potent TYR inhibitor AI10-a2 , highlighting AI’s capacity to uncover nonintuitive activity cliffs despite greater output variability. Systematic comparison revealed that the AI model offers exploratory diversity, whereas expert-guided optimization provides predictable improvements in activity and developability. In summary, starting from an AI-generated lead and subsequently integrating both expert-guided and AI-driven structural optimization strategies, these findings further underscore that combining AI technologies with experts’ medicinal chemistry insights can substantially accelerate the discovery of viable candidate compounds.