Discovery of highly potent TNFα inhibitors using virtual screen

Qi Shen  ¹ , Jing Chen  ² , Qian Wang  ³ , Xiaobing Deng  ⁴ , Ying Liu  ² , Luhua Lai  ⁵

• ¹ Center for Quantitative Biology, Peking University, Beijing 100871, China.
• ² Center for Quantitative Biology, Peking University, Beijing 100871, China; BNLMS, State Key Laboratory of Structural Chemistry for Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
• ³ BNLMS, State Key Laboratory of Structural Chemistry for Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
• ⁴ Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
• ⁵ Center for Quantitative Biology, Peking University, Beijing 100871, China; BNLMS, State Key Laboratory of Structural Chemistry for Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China. Electronic address: lhlai@pku.edu.cn.

Abstract

Tumor necrosis factor-α (TNFα) is a validated therapeutic target for various autoimmune disorders such as rheumatoid arthritis and asthma. All TNFα inhibitors currently on the market are biologics, making the development of small molecule alternatives in urgent need. However, only a few successful cases of direct TNFα antagonization in vitro have been reported. Here, we present the identification of several small molecule candidates able to effectively reduce TNFα activity in vitro and in cell assays. Virtual screen targeting TNFα dimer was performed on the SPECS database and 101 compounds were selected for experimental testing. Two compounds, 1 and 2, displayed considerable inhibitory activity. Follow-up structure-activity relationship analysis of compound 1 identified 3 molecules with low micromolar cell-level inhibitory activity. Compound 11 showed an IC50 value of 14 μM, making it among the most potent TNFα small molecule inhibitors reported. These compounds provide new scaffolds for future development of small molecule drugs against TNFα.

Keywords: Small molecule inhibitors; TNFα; Virtual screen.