Design, synthesis and activity evaluation of a novel PPARα agonist based on virtual screening

  • Bioorg Med Chem Lett. 2026 Jun:135:130585. doi: 10.1016/j.bmcl.2026.130585.
Yutong Niu  1 ,  Weinan Wang  2 ,  Yiqian Xie  1 ,  Li Zhang  3 ,  Xingyong Liu  3 ,  Likun Gong  4 ,  Jing Chen  5 ,  Zhili Zuo  6
Affiliations
  • 1. School of Chemical Engineering, Sichuan University of Science & Engineering, Zigong 643000, China; Zhejiang Key Laboratory of Intelligent Drug Discovery and Development, School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, UCAS, Hangzhou 310024, China.
  • 2. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3. School of Chemical Engineering, Sichuan University of Science & Engineering, Zigong 643000, China.
  • 4. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: [email protected].
  • 5. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: [email protected].
  • 6. Zhejiang Key Laboratory of Intelligent Drug Discovery and Development, School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, UCAS, Hangzhou 310024, China. Electronic address: [email protected].
PMID: 41692311 DOI: 10.1016/j.bmcl.2026.130585
Abstract

Peroxisome Proliferator-activated Receptor α (PPARα) represents a critical therapeutic target for dyslipidemia. To discover novel scaffold agonists, we used Pemafibrate as a template to construct a focused chemical library with the infiniSee software. An integrated virtual screening approach, including molecular docking, MM-GBSA binding free energy calculations, ADMET profiling, and visual inspection, was applied to identify a hit compound. Subsequent structural optimization led to the synthesis of 40 derivatives. Among the tested compounds, XYQ3-B11 was identified as the most potent PPARα Activator. In the luciferase reporter assay, XYQ3-B11 exhibited an EC50 value of 8.33 μM, better than the reference agonist WY14643 (EC50 = 16.10 μM). Notably, XYQ3-B11 possesses a distinctive hybrid architecture, comprising a central pyridine ring, a 2-fluorobenzoate moiety, and an indole-derived side chain. These findings highlight XYQ3-B11 as a promising novel chemotype for the start of development of PPARα agonists.

Keywords
PPARα agonist; Structural modification; Synthesis; Virtual screening.
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