Georgia Tech To Develop Tools To Improve Drug Efficacy

$2.44M NIH grant will enable comprehensive annotation of genes related to disease.

The National Institutes of Health has awarded College of Sciences’ Jeffrey Skolnick a $2.44M grant over five years. The Mary and Maisie Gibson Chaired professor in the School of Biology and a Georgia Research Alliance Eminent Scholar in Computational Systems Biology, Skolnick aims to develop tools to comprehensively annotate the parts of the human genome that are translated into proteins, known as the exome. Ultimately, the goal is to predict other uses of drugs already approved by the Federal Drug Administration (FDA) and thus accelerate the treatment of patients with intractable diseases.

With the availability of rapid and low-cost genome sequencing, about 228,000 human exomes would have been sequenced by the end of 2014, said Francis de Souza, president of Illumina, the maker of DNA-sequencing machines back in 2014. These sequences carry huge information that could be applied to personalized medicine, Skolnick says. However, this potential is unrealized, because many genetic variations in the exome are of unknown significance. With appropriate tools to annotate the exome, scientists can determine which variations might be significantly related to disease and what diseases might be caused by certain variations.

Skolnick, who is also director of the College of Sciences’ Center for the Study of Systems Biology, is an expert in bioinformatics. His lab has been developing and using algorithms to predict protein structure and function, as well as protein–small molecule interactions. The $2.44M NIH grant will help create a suite of tools to describe fully the effects of variations in exome genes on the amino acid compositions and structures of their expressed proteins.

Low-resolution predicted protein structures from bioinformatics analyses can infer disease-associated variations and can be used for virtual ligand screening, Skolnick’s research has shown. “In practice this means that we can predict off-target uses of FDA-approved drugs for the majority of human proteins,” Skolnick says. “We are the first group to do this for most human proteins and to use predicted structures to do so.”

Skolnick’s lab also has demonstrated that the number of unique small-molecule-ligand-binding pockets in the human proteome is only about 500.  Naturally evolved ligands fit these binding pockets more or less perfectly. On the other hand, most drug molecules are promiscuous, binding to different proteins, albeit imperfectly. “This explains one major reason that drug side effects occur,” Skolnick says.

Using the NIH grant, Skolnick’s group will elucidate the design principles underlying protein structure and function. And then they will use those principles to find other diseases that FDA-approved drugs could treat. Among the drugs they will examine are granisetron (Kytril), an anti-nausea agent; progesterone, a female hormone; acetaminophen, a pain reliever; and naproxen an anti-inflammatory and analgesic agent. Diseases of interest include cancer, pain, cardiovascular diseases, neurological diseases, cystic fibrosis, and diseases caused by genetic variations.

The grant comes from a new NIH program – Maximizing Investigators’ Research Award (MIRA) – to support research that falls within the mission of the National Institute of General Medical Sciences (NIGMS). According to NIGMS, “The goal of MIRA is to increase the efficiency and efficacy of NIGMS funding by providing investigators with greater stability and flexibility, thereby enhancing scientific productivity and the chances for important breakthroughs.” The award to Skolnick is among the first by the MIRA program, which is in pilot-testing phase.

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