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Updated: Jan 22, 2026

Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis
Published on: June 20, 2025
Structure-based discovery of a specific TLR1-TLR2 small molecule agonist from the ZINC drug library database
Zhipeng Chen1, Xiaohong Cen, Junjie Yang
1Guangdong Provincial Key Laboratory of New Drug Screening, State Key Laboratory of Organ Failure Research and Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China. Chengk@smu.edu.cn.
Abstract:
We report herein the identification of urea structure-like small molecules by structure-based virtual screening of 10.5 million compounds. Based on a variety of HEK-Blue hTLRs reporter cell assay results, we validated a TLR1/2-specific small molecule agonist, ZINC666243 (SMU127), with EC50 of 0.55 ± 0.01 μM. SMU127 stimulates NF-κB activation and promotes TNFα secretion in human macrophages and mononuclear cells. Moreover, the in vivo assay indicated that SMU127 could inhibit the growth of breast cancer tumors in BABL/c mice. This work has shown for the first time that a small molecule TLR1/2 agonist can inhibit breast cancer in vivo.
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