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

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

Journal

European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510

Informations de publication

Date de publication:
19 Sep 2024
Historique:
received: 26 08 2024
revised: 12 09 2024
accepted: 14 09 2024
medline: 28 9 2024
pubmed: 28 9 2024
entrez: 27 9 2024
Statut: aheadofprint

Résumé

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 (IC

Identifiants

DOI: 10.1016/j.ejmech.2024.116888 PMID: 39332383
pubmed: 39332383
pii: S0223-5234(24)00769-4
doi: 10.1016/j.ejmech.2024.116888
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

116888

Informations de copyright

Copyright © 2024 Elsevier Masson SAS. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Auteurs

Huahao Wang (H)

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.

Liran Lei (L)

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.

Hao Guo (H)

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.

Kejia Xu (K)

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.

Quan Liu (Q)

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.

Hui Cao (H)

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.

Jinping Hu (J)

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.

Shuainan Liu (S)

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.

Dongfeng Zhang (D)

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.

Classifications MeSH