2. Academic Validation
  3. Discovery of the small molecular inhibitors against sclerostin loop3 as potential anti-osteoporosis agents by structural based virtual screening and molecular design

Discovery of the small molecular inhibitors against sclerostin loop3 as potential anti-osteoporosis agents by structural based virtual screening and molecular design

  • Eur J Med Chem. 2024 May 5:271:116414. doi: 10.1016/j.ejmech.2024.116414.
Sifan Yu 1,  Weifeng Huang 2,  Hao Zhang 2,  Yinfeng Guo 2,  Baoting Zhang 3,  Ge Zhang 4,  Jinping Lei 5
Affiliations

Affiliations

  • 1 Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, Hong Kong Baptist University, Hong Kong SAR, China. Electronic address: sifanyu@cuhk.edu.hk.
  • 2 Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
  • 3 School of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • 4 Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, Hong Kong Baptist University, Hong Kong SAR, China. Electronic address: zhangge@hkbu.edu.hk.
  • 5 Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China; State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China. Electronic address: leijp@mail.sysu.edu.cn.
PMID: 38677061 DOI: 10.1016/j.ejmech.2024.116414
Abstract

Sclerostin is a secreted glycoprotein that expresses predominantly in osteocytes and inhibits bone formation by antagonizing the Wnt/β-catenin signaling pathway, and the loop3 region of sclerostin has recently discovered as a novel therapeutic target for bone anabolic treatment without increasing cardiovascular risk. Herein, we used a structural based virtual screening to search for small molecular inhibitors selectively targeting sclerostin loop3. A novel natural product hit ZINC4228235 (THFA) was identified as the sclerostin loop3-selective inhibitor with a Kd value of 42.43 nM against sclerostin loop3. The simplification and derivation of THFA using molecular modeling-guided modification allowed the discovery of an effective and loop3-selective small molecular inhibitor, compound (4-(3-acetamidoprop-1-yn-1-yl)benzoyl)glycine (AACA), with improved binding affinity (Kd = 15.4 nM) compared to the hit THFA. Further in-vitro experiment revealed that compound AACA could attenuate the suppressive effect of transfected sclerostin on Wnt signaling and bone formation. These results make AACA as a potential candidate for development of anti-osteoporosis agents without increasing cardiovascular risk.

Keywords

Anti-osteoporosis; Sclerostin; Selective; Small molecular inhibitors; Structural based virtual screening.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-163513
    99.39%, Sclerostin Inhibitor
    Wnt