In a new study entitled “Computational re-engineering of Amylin sequence with reduced amyloidogenic potential”, computational scientists designed a new program that will foster the development of drugs for misfolded proteins-associated diseases, including Alzheimer’s and Type II Diabetes. The study was published in the BMC Structural Biology journal.
Aggregates of incorrectly folded proteins (misfolded proteins) is a crucial event contributing to the development of several neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, but also Type II Diabetes. These insoluble protein aggregates, referred to as amyloid fibrils, have been observed to buildup in multiple organs, including the brain, heart and pancreas, and prevent their normal functioning. Hence, developing medications that target these toxic protein aggregates is a crucial strategy. Notably, however, the process for developing such drugs is fastidious and prone to trial and error.
Now, a team of researchers at McGill University developed a computer program that promises to speed the process of drug discovery for amyloid fibrils-associated diseases. Specifically, the FibrilMutant program searches for mutations that destabilize amyloid fibrils but maintain the protein native form. By identifying these weak spots, researchers can introduce a genetic mutation that weakens fibrils stability, which decreases its toxicity.
Mohamed Smaoui, a McGill postdoctoral fellow and study first author noted, “Within the space of a week, by using our programs and a supercomputer, we were able to look at billions of possible ways to weaken the bonds within these toxic protein strands. We narrowed it down to just 30 — 50 possibilities that can now be explored further. Typically biochemists can spend months or years in the lab trying to pinpoint these promising mutations.”
Using their newly developed program, the team tested a medical compound – Symlin – used by diabetes patients to enhance insulin action but whose long-term use causes the buildup of amyloid fibrils in patients’ pancreas. The team was able to identify, using FibrilMutant program, a few genetic modifications that may reduce its toxicity.
Prof. Jérôme Waldispühl, at School of Computer Science and study lead author commented on these findings, “Computers are transforming the way that drugs are being developed. Amyloid research has accelerated in the last 10 years. But computers may prove to be the key to finding better medications for a whole range of systemic and neurodegenerative diseases, from arthritis to Parkinson’s. Without supercomputers and programs of this kind, it would take much longer and be much more expensive to do this kind of research and come up with these possible solutions to the problem.”