In Silico identification of novel phytochemicals that target SFRP4: An early biomarker of diabesity.
Asim RehmanShazia Anwer BukhariNaheed AkhterMuhammad Abdullah Ijaz HussainZunera ChauhdaryPublished in: PloS one (2023)
The simultaneous coexistence of complicated metabolic conditions like obesity and diabetes within an individual is known as diabesity. Obesity is the key factor for many chronic diseases, including insulin resistance and type 2 diabetes (T2D). Metabolic stress due to nutrient overload releases different inflammatory mediators. Secreted frizzled-related protein 4 (SFRP4) is also an inflammatory mediator that impairs insulin secretion. SFRP4 acts as an early biomarker for diabesity expressed with interleukin-1 beta (IL-1β) in the adipose tissues that hinder the exocytosis of insulin-secreting granules from the pancreatic β-cells and is a potential target for preserving β-cell dysfunction and the diabesity treatment. The current study aimed to screen potential bioactive compounds targeting and inhibiting the diabesity-linked SFRP4 protein through an in silico approach. The three-dimensional (3D) structure of human SFRP4 was predicted through comparative modeling techniques and evaluated by various online bioinformatics tools. The molecular docking and MD simulation investigations were carried out against phytochemicals with anti-diabetic and anti-obesity properties to shortlist the best SFRP4 inhibitor. Hesperetin, Curcumin, Isorhamnetin, Embelin, Epicatechin, and Methyl Eugenol interacted strongly with SFRP4 by displaying zero RMSD and binding affinities of -6.5, -6.4, -6.3, -5.3, -6.3 and -5.8 kcal/mol respectively. Additionally, the root mean square fluctuation and root mean square deviation graphs from the MD simulation results demonstrated that hesperetin has good variations throughout the simulation period as compared to others. This dynamic stability and control behavior of hesperetin, when it interacts with SFRP4, shows that it has the potential to modulate the function and activity of the protein. Therefore, hesperetin is identified as an effective and top drug candidate through this analysis for preserving beta-cell function and treating diabesity by targeting SFRP4. The findings of this study could be useful in the design and development of diabesity drugs.
Keyphrases
- type diabetes
- insulin resistance
- molecular docking
- glycemic control
- metabolic syndrome
- high fat diet induced
- adipose tissue
- oxidative stress
- weight loss
- high fat diet
- polycystic ovary syndrome
- gene expression
- cardiovascular disease
- weight gain
- induced apoptosis
- signaling pathway
- molecular dynamics simulations
- stem cells
- endothelial cells
- emergency department
- protein protein
- small molecule
- body mass index
- human health
- amino acid
- drug induced
- bone marrow
- cell therapy
- health information
- induced pluripotent stem cells
- adverse drug
- virtual reality
- smoking cessation
- cancer therapy