Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • br Conclusions br Conflicts of interest br Funding The resea

    2021-10-25


    Conclusions
    Conflicts of interest
    Funding The research work was partially supported by National Science Center (Contract Grant Number: UMO-2015/19/B/NZ1/00332).
    Introduction Frusectose-1, 6-bisphosphatase (FBPase) has long been recognized as a potential therapeutic target for the treatment of type 2 JIB-04 (T2DM). As a rate-limiting enzyme of the gluconeogenesis (GNG) pathway, it catalyzes the hydrolysis of fructose-1, 6-bisphosphate to fructose-6-phosphate. Thus, the inhibition of gluconeogenesis is a useful approach in reducing increased blood glucose levels in patients with T2DM. FBPase inhibitors would lower blood glucose levels by reducing hepatic glucose output and are expected to be a novel class of drugs for the treatment of T2DM [1], [2], [3], [4], [5], [6], [7], [8]. In recent years, a number of FBPase inhibitors have appeared in the patent and primary literatures [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28]. Among them, Qun Dang et al. synthesized a series of benzimidazole-based derivatives as potent, selective FBPase inhibitors [13]. In addition, An X-ray crystal structure of a similar analogue inhibitor in complex with human liver FBPase have been determined which provide important information about the interaction with the residues of the binding site [21]. Recently many studies have been published in which the combination of receptor-based methods and 3D-QSAR. The three-dimensional structure of a target protein, along with a docking protocol is used to guide alignment selection for comparative molecular field analysis. It is quite appealing to combine the accuracy of a receptor-based alignment with the computational efficiency of a ligand-based method. Receptor structures, either experimentally resolved or obtained by homology modeling, can provide important information that is critical for an alignment in CoMFA, while QSAR can provide better prediction of binding energies [29], [30]. In this study, we applied this receptor-based 3D-QSAR technique to a set of 47 FBPase inhibitors which have been recently developed [13]. The crystal structure of the catalytic domain of human liver FBPase together with an automatic docking program was used to determine the molecular alignment of the ligands. The 3D-QSAR model obtained by this way yielded a high correlation between the experimentally determined binding affinity and the calculated molecular interaction fields. It was shown that the receptor-based 3D-QSAR yields a better prediction of the binding affinity than using an interaction energy-based model or a ligand-based 3D-QSAR analysis. Encouraged by these results the receptor-based 3D-QSAR model should now be used for the screening and prediction of novel inhibitors for FBPase.
    Computational details
    Results and discussion
    Conclusion
    Acknowledgments
    Type 2 diabetes mellitus (T2DM), which accounts for more than 90% of all diabetes, is characterized by high levels of glucose in the plasma. The global incidence of this disease is predicted to rise to more than 366 million by the year 2030. T2DM usually leads to complications such as retinopathy, nephropathy, and neuropathy. Clinical studies have suggested that fasting hyperglycemia in T2DM is associated with excessive glucose production through gluconeogenesis. Thus, the inhibition of gluconeogenesis is a potentially useful approach to reducing the increased blood glucose levels in patients with T2DM. Fructose-1,6-bisphosphatase (FBPase), which is predominantly expressed in the liver and the kidney and catalyzes the hydrolysis of fructose-1,6-bisphosphate (F1,6BP) to fructose-6-phosphate (F6P), is one of the rate-limiting enzymes of gluconeogenesis. FBPase is a homotetramer and exists in two distinct conformational states, an active R-state and an inactive T-state. F1,6BP and F6P in combination with metal cations stabilize the active R-state, while adenosine 5′-monophosphate (AMP, ) and substrate analogue fructose-2,6-bisphosphate (F2,6BP) synergistically stabilize the inactive T-state. AMP and/or F2,6BP are natural inhibitors of FBPase which bind to the allosteric site and the substrate-binding site, respectively, and control blood glucose levels by regulating the activity of FBPase. FBPase inhibitors would lower blood glucose levels by reducing hepatic glucose output and are expected to be a novel class of drugs for the treatment of T2DM.