Research Article Details

Article ID: A50045
PMID: 35547362
Source: PPAR Res
Title: Molecular Dynamics Simulation and Essential Dynamics of Deleterious Proline 12 Alanine Single-Nucleotide Polymorphism in PPARγ2 Associated with Type 2 Diabetes, Cardiovascular Disease, and Nonalcoholic Fatty Liver Disease.
Abstract: Background. Peroxisome proliferator-activated receptor-γ (PPARγ) gene is located at 3p25 position. PPARγ functions as the master regulator of glucose homeostasis and lipoprotein metabolism, and recent studies have reported that it is involved in various metabolic diseases such as diabetes mellitus, hyperlipidemia, coronary artery disease (CAD), and nonalcoholic fatty liver disease (NAFLD). PPARγ1 and PPARγ2 are necessary for the development of adipose tissue and insulin sensitivity regulation. But PPARγ2 is the isoform that was controlled in response to nutrient intake and obesity. Methodology. In this study, we used computational techniques to show the impact of Pro12Ala polymorphism on PPARγ2. The 3-D structure of PPARγ2 was modeled using I-TASSER server. The modeled structure was validated with the ZLab server, and the mutation was created with SPDB viewer. Stability prediction tools were used. Molecular dynamics simulation (MDS) was used to understand the structural and functional behavior of the wild type and mutant. Essential dynamics was also applied. Results and Conclusions. Stability prediction tools were showed that this mutation has a destabilizing effect on the PPARγ2 structure. The RMSD, RMSF, Rg, SASA, and DSSP were in line with H-bond results that showed less flexibility in the mutant structure. Essential dynamics was used to verify MDS results. Pro12Ala polymorphism leads to rigidity of the PPARγ2 protein and might disturb the conformational changes and interactions of PPARγ2 and results in type 2 diabetes mellitus (T2DM), CAD, and NAFLD. This study can help scientists to develop a drug therapy against these diseases.
DOI: 10.1155/2022/3833668

Strategy ID Therapy Strategy Synonyms Therapy Targets Therapy Drugs

Target ID Target Name GENE Action Class UniProtKB ID Entry Name

Diseases ID DO ID Disease Name Definition Class
I05 9352 Type 2 diabetes mellitus A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus Details
I14 9970 Obesity An overnutrition that is characterized by excess body fat, traditionally defined as an elevated ratio of weight to height (specifically 30 kilograms per meter squared), has_material_basis_in a multifactorial etiology related to excess nutrition intake, decreased caloric utilization, and genetic susceptibility, and possibly medications and certain disorders of metabolism, endocrine function, and mental illness. https://en.wikipedia.org/wiki/Obesity disease of metabolism/acquired metabolic disease/ nutrition disease/overnutrition Details

Drug ID Drug Name Type DrugBank ID Targets Category Latest Progress
D579 Emfilermin Miscellany -- adipocytes Enhance lipid metabolism Under investigation Details
D199 L-alanine Chemical drug DB00160 KYNU -- Failed in clinical trials Details
D328 Serine Chemical drug DB00133 SRR Improve insulin resistance Under clinical trials Details
D018 Aspirin Chemical drug DB00945 AKR1C1 inhibitor; PCNA downregulator Enhance lipid metabolism Under clinical trials Details
D182 Insulin Biological drug DB00030 INSR agonist; CPE modulator&product of -- Under clinical trials Details
D248 Obeticholic Acid Chemical drug DB05990 NR1H4 activator; NR1H4 agonist; FXR agonist Enhance lipid metabolism Approval rejected Details