Discovery of novel fructose-1,6-bisphosphatase inhibitors bearing benzimidazole scaffold using a dual-ligand molecular docking model

  • Eur J Med Chem. 2024 Dec 5:279:116888. doi: 10.1016/j.ejmech.2024.116888.
Huahao Wang  1 ,  Liran Lei  2 ,  Hao Guo  1 ,  Kejia Xu  2 ,  Quan Liu  2 ,  Hui Cao  2 ,  Jinping Hu  3 ,  Shuainan Liu  4 ,  Dongfeng Zhang  5
Affiliations
  • 1. Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, China.
  • 2. Department of Pharmacology, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing, 100050, China.
  • 3. Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing, 100050, China.
  • 4. Department of Pharmacology, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing, 100050, China. Electronic address: [email protected].
  • 5. Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, China. Electronic address: [email protected].
PMID: 39332383 DOI: 10.1016/j.ejmech.2024.116888
Abstract

Fructose-1,6-bisphosphatase (FBPase) is an emerging target in gluconeogenesis, inhibitors of which would be an effective treatment for elevated fasting blood glucose in patients with type 2 diabetes. Based on the lead compound G-1 (FBPase 10 μM inhibition = 64.3 %) and according to the X-ray crystal structure of FBPase, we designed and validated an innovative molecular docking method based on the dual-ligand model to explore the interactions between two identical ligands in neighboring targets. Based on the dual-ligand molecular docking model, a novel compound 45 bearing a benzimidazole scaffold was identified to show increased inhibitory activity against FBPase (IC50, 2.08 μM). An oral pyruvate tolerance test in ICR mice showed that 45 had a potent inhibitory effect on gluconeogenesis similar to that of metformin when administered as a single dose in vivo. Compound 45 did not inhibit the common subtypes of the human Cytochrome P450 system, indicating that it may have a reduced propensity for drug-drug interactions. The findings of this study may pave the way for further development of FBPase inhibitors with novel structural features, improved activity, and good druggability.

Keywords
Benzimidazole scaffold; Dual-ligand molecular docking; Fructose-1,6-bisphosphatase; Oral pyruvate tolerance test; Type 2 diabetes mellitus.
Products