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

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

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: liusn@imm.ac.cn.
  • 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: zdf@imm.ac.cn.
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.

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