In-Silico Design of Novel Glucagon-Like Peptide 1 Mutants as Candidate for New Peptide Agonist Drugs

Abstract

The type 2 diabetes mellitus (T2DM) is a type of diabetes mellitus with the highest number of patients, covering 90-95% of the total diabetes mellitus case in the world. (American Diabetes Association 2012; Olokoba et al. 2012). This chronic metabolic disease is characterized by high blood sugar levels (hyperglycemia) caused by insulin resistance (reduction of insulin secretion or insulin function) (Weyer et al. 1999). The insulin secretion in the body occurs through various mechanisms, one of them depends on the role of incretin hormone. The Incretin hormone itself is a gut hormone that can stimulate insulin secretion in the body. One of incretin hormone that has a significant role in insulin secretion is GLP-1. Protein GLP-1 (Glucagon-like peptide 1) is an incretin hormone that mainly produced in enteroendocrine L cells of the gut shortly after eating or increasing glucose in the blood (Doyle and Egan 2007). This protein stimulates insulin secretion in the body by activating the GLP-1R agonists in pancreatic β cells to encourage adenylyl cyclase activation and cAMP (cyclic Adenosine Mono Phosphate) generation. This cAMP production will activate PKA (Protein Kinase A) and EPAC (Exchange Proteins Activated by cAMP) that play an essential role in insulin secretion (Meloni et al. 2012). The GLP-1 performs critical functions in the body such as: stimulating the insulin secretion from the pancreatic β-cells, stimulating the biosynthesis of insulin and insulin sensitivity, increasing the β-cell proliferation and apoptosis protection, inhibiting the glucagon secretion, gastric emptying, and food intake (Drucker 2001; Li et al. 2010; Quoyer et al. 2010). Those specific functions make the GLP-1 protein as one alternative that can be applied in treating the T2DM and as primary therapy for metabolic diseases such as obesity (Ahrén and Ahren 2011; Mostafa et al. 2015; Anderberg et al. 2016). The GLP-1 protein ABSTRACT