Using Artificial Intelligence to Learn More about RAGE Receptors

Published March 30, 2020

By Kimberly Mann Bruch, SDSC Communications

Receptor Advanced Glycation End-products (RAGEs) were first characterized in 1992 and thought to be linked to several chronic diseases including Alzheimer’s, diabetes, and congestive heart failure. They are the focus of a new study by researchers affiliated with the San Diego Supercomputer Center (SDSC) at UC San Diego, which describes the use of artificial intelligence machine learning tools to demonstrate a potential RAGE inhibitor that has better efficacy and fewer side effects.

The paper, published in January’s Physical Biology journal, is the result of studies by SDSC researchers Igor Tsigelny and Valentina Kouznetsova, as well as David Huang, a high school student participant in SDSC’s annual Research Experience for High School Students (REHS) summer internship program.

Glycation, which is the covalent attachment of a sugar, such as glucose, fructose, and their derivatives to protein, DNA or lipid amino groups, has been shown to be a key factor in AGE creation in the organism, according to the researchers. Previous inhibitors were developed mostly based on traditional pharmacophore design of compounds that block AGEs binding to RAGE.

Instead of relying solely upon pharmacophore-based research, Tsigelny, Kouznetsova, and Huang’s work used artificial intelligence (AI) to discover a new deep learning-based method of an inhibitor design. The new potential drug candidates were determined by the researchers to possibly be more effective, while having fewer negative side effects.

Fostering Student Involvement in Scientific Research

“The serious input to this publication was done by David Huang,” said Tsigelny. “We were thrilled to have an REHS student work with us on this published study, which demonstrates the potential of a broad family of deep-learning techniques on bioactivity predictions. David’s work was useful in allowing us to explain how inhibitors bind to RAGE – transmembrane receptors – and prevent binding of many advanced glycation end products (AGEs), which have been shown to enhance a large set of diseases.”

Huang has worked with Tsigelny and Kouznetsova on several other projects, including collaborating with other students to present a paper regarding treatment of diabetic cataracts.

“It is useful for our lab to have students working with us as they always present unique ideas that otherwise we might not think of,” said Tsigelny. “We have been really pleased with David’s work and look forward to watching his academic endeavors flourish.”

In addition to their positions at SDSC, Tsigelny and Kouznetsova are also affiliated with UC San Diego’s Moores Cancer Center. Tsigelny is also affiliated with the UC San Diego Department of Neurosciences and CureMatch Inc.

Alternatives to Inhibitors: Food as Medicine While their recent study focused on future development of RAGE inhibitors, SDSC researchers are also working on studies how food can be used as a medicine. In particular, Kouznetsova said that AGEs are formed in organisms with high levels of blood sugar and that they are also formed in products during cooking. “Foods highest in AGEs include barbequed and roasted meat, delicious crusts of breads and pies, fried eggs, some cheeses, butter, and much more,” said Kouznetsova. “However, in individuals having a vegetarian diet, levels of AGEs can still be high.” Moreover, the formation of AGEs comes with the ageing process, noted Kouznetsova. As humans age, their bodies typically experience an increase in the formation of AGEs and when linked with the receptors cause aging signs in human bodies in areas such as the skin, vessels, bones, and nerves. Many studies have shown that a healthy diet aids in slowing the aging process while bolstering disease prevention. However, with advancing age or disease progression, AGEs accumulation grows and cannot be stopped with correct nutrition only, noted Kouznetsova. In these cases, RAGE inhibitors are necessary, and the work conducted by Tsigelny, Kouznetsova, and Huang with this novel study showcased the potential for a more effective drug design.

 

About SDSC

As an Organized Unit of the University of California San Diego, SDSC is considered a leader in data-intensive computing and cyberinfrastructure, providing resources, services, and expertise to the national research community, including industry and academia. Cyberinfrastructure refers to an accessible, integrated network of computer-based resources and expertise, focused on accelerating scientific inquiry and discovery. SDSC supports hundreds of multidisciplinary programs spanning a wide variety of domains, from earth sciences and biology to astrophysics, bioinformatics, and health IT. SDSC’s petascale Comet supercomputer is a key resource within the National Science Foundation’s XSEDE (Extreme Science and Engineering Discovery Environment) program.