The researchers found that the insulin analog (green) acts faster without reducing ability to bind to the insulin receptor (light blue).
Image credit: University of Basel Department of Chemistry
The researchers - from Switzerland, the United States, and Australia - found that they could speed up the disassembly and release of insulin from its complex structure to its available form by replacing a single hydrogen atom with an iodine atom in its molecular structure.
Insulin is a small protein that regulates blood glucose by passing signals into cells. In the body, it exists in two forms: a complex one for storage and a simpler one for action.
In its storage form, insulin exists as a zinc-bound complex of six identical molecules called a hexamer. The simple, active form is an unbound single molecule, or monomer.
When the body requires insulin to regulate blood sugar, the hexamer disassembles into monomers.
The insulin molecule then has to bind to a partner molecule - known as the insulin receptor - that sits on the surface of cells. This binding allows signals from the insulin to pass into the cell.
For some time, researchers have been experimenting with ways to control this disassembly process to improve the treatment of diabetes - a disease that occurs when insulin production is impaired or when the body cannot use it properly.
Researchers use various approaches to explore and discover new ways to fight disease with molecules that do not exist in nature. This includes creating synthetic versions, or analogs, of naturally occurring compounds.
Protein engineering involves altering the structure and function of proteins - the chemical workhorses of the organism - using only a computer or through evolution in the laboratory.
In the new study, Markus Meuwly, a chemistry professor at the University of Basel in Switzerland, and colleagues experimented with various insulin analogs by strategically replacing individual atoms in the molecular structure of natural insulin.
Promising approach for optimizing medicinal compounds
Computer simulations based on quantum chemistry and molecular dynamics, which model processes in the body involving insulin, allowed the team to observe the properties of the analogs.
They then carried out laboratory experiments to confirm the properties observed in the computer simulations. These experiments used methods such as crystallography and nuclear magnetic resonance.
The researchers discovered that exchanging one hydrogen atom for one iodine atom improved the availability of insulin but did not change its affinity for the insulin receptor.
It is quite conceivable, say the researchers, that their insulin analog - which differs from natural insulin by only a single atom - has clinical potential as a new drug.
The use of halogen atoms - a group that includes fluorine, chlorine, bromine, and iodine - is a promising approach for optimizing compounds in medicinal chemistry, say the researchers, who add:
"Inspired by quantum chemistry and molecular dynamics, such 'halogen engineering' promises to extend principles of medicinal chemistry to proteins."