Your browser doesn't support javascript.
loading
Identification of novel RANKL inhibitors through in silico analysis.
Jiang, Yingying; Luo, Xiaogang; Zheng, Zhanpeng; Wen, Shun; Gao, Hongwei; Xu, Cheng; Jiang, Min; Wang, Siyuan.
Afiliación
  • Jiang Y; College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, China; Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical Scho
  • Luo X; College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, China.
  • Zheng Z; College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, China.
  • Wen S; College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, China.
  • Gao H; China School of Life Science, Ludong University, Yantai, Shandong 264025, China.
  • Xu C; Institute of Microalgae Synthetic Biology and Green Manufacturing, School of Life Sciences, Jianghan University, Wuhan, Hubei 430056, China. Electronic address: xucheng_2007@jhun.edu.cn.
  • Jiang M; Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: jiangm263@163.com.
  • Wang S; College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, China. Electronic address: wangsiyuan@sztu.edu.cn.
Bioorg Chem ; 153: 107826, 2024 Sep 16.
Article en En | MEDLINE | ID: mdl-39299177
ABSTRACT
Receptor activator of nuclear factor-κB ligand (RANKL) is considered the principal regulator of osteoclast differentiation. Therefore, strategies interfering with the RANKL-RANK signaling pathway may effectively inhibit osteoclast differentiation and mitigate bone resorption. Consequently, RANKL has become a promising target for new drug design strategies. Despite extensive research on specific drugs and antibodies, only a few have shown efficacy in treating osteoporosis. To address this challenge, we aimed to explore new approaches for designing drugs for osteoporosis. In this study, a 3D quantitative structure-activity relationship (QSAR) pharmacophore model was built for RANKL with reference to known inhibitor IC50 values. The optimal pharmacophore model was then employed as a 3D query to screen databases for novel lead compounds. The obtained compounds were subjected to ADMET and TOPKAT analyses to predict drug pharmacokinetics and toxicity. Molecular docking and de novo evolution approaches were applied to verify the docking binding affinities of the compounds. Five candidate compounds were subjected to further in vitro analyses to assess their anti-osteoporotic effects, among which compound 4 demonstrated significant inhibitory activity, achieving an inhibitory rate of 92.6 % on osteoclastogenesis at a concentration of 10 µM. Subsequent molecular dynamics (MD) simulations to assess the stability and behavior of compound 4 and its evolved variant, ZINC00059014397_Evo, within the RANKL binding site revealed that the variant is a potential therapeutic agent for targeting osteoclasts. This study offers valuable insights for developing next generation RANKL inhibitors for osteoporosis treatments.
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Bioorg Chem Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Bioorg Chem Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos