Insulin-mediated GLUT4 translocation via small molecule binding of UNC119B for the treatment of diabetes mellitus

Type II diabetes is a disease that occurs when blood glucose levels are no longer regulated due to impaired insulin signaling. In fat and muscle cells, glucose transporters, referred to as GLUT4, transport glucose into cells. Without the insulin signal, GLUT4 is unable to travel to the surface of cells, or translocate, and transport glucose for storage. To treat the issue of the impaired insulin signaling and lower blood glucose levels through GLUT4 translocation, small molecules were identified from a large group that screened for increases in GLUT4 translocation in the presence of insulin. As a result of this screen, the second generation insulin sensitizer named C59 was synthesized and undergoes modification to become more water soluble and more potent. Several different compounds derived from making modifications to different parts of C59, novel drug, were tested computationally for their ability to bind UNC119B, the drug target for treating insulin insensitivity in type II diabetes. Within the docking program, each compound had multiple poses which are attributed to the lowest energy and best probability of binding. The best poses are ranked via an interface score, also called a docking score and the results led to the selection of different derivatives of a novel drug C59. The C59 derivatives, or modified drugs that look and are shaped similar to C59, were made using synthetic chemical processes and tested in cells that confirmed whether the compound increased GLUT4 translocation, which results in the lowering of blood glucose. Afterward, the effective concentrations of the compounds from the cell data was compared with the calculated properties of the compounds. Each compound has a unique set of traits that contribute to its performance as a drug, thus understanding if they have a trend is beneficial in making better compounds. Lastly, the top two compounds were made into cyclodextrin complexes to remedy water solubility and drug administration issues.