Cheminformatics Expert Awarded NIH Grant to Study “Druggable Genome”

Knowing the size of the human genome, it is exciting to consider just how many molecular targets could represent an opportunity for therapeutic intervention. As part of an NIH Common Fund project called Illuminating the Druggable Genome (IDG), Stephan Schürer, Ph.D., research associate professor of molecular and cellular pharmacology, has received part of a $5.8 million grant established to discover many of these targets.

For the multifaceted study of the “druggable genome” – the subset of the nearly 30,000 genes in the human genome that express proteins able to bind drug-like molecules — Schürer and his team at the Center for Computational Science will serve as an integral part of the Knowledge Management Center, designed to develop an integrated informatics solution that encompasses data accrual, analysis, data-driven prioritizations and abstraction that will help identify knowledge gaps in these proteins. In addition to the Knowledge Management Center, the project also includes several Technology Development and Screening Centers.

“The basic idea of the IDG project is to accelerate the discovery of compounds for parts of the genome that so far is orphan — for which there are no drugs — and among that orphan genome, to prioritize the most relevant targets with respect to diseases and drug targetability,” said Schürer, lead chemoinformatics scientist at the Center for Computational Science, who is the principal investigator of the University of Miami group. “The Knowledge Management Center will integrate large amounts of data information and knowledge via a variety of technologies to facilitate this project. Specifically it will enable researchers to prioritize understudied but disease-relevant drug targets.”

Schürer brings to the project an extensive research repertoire of computer-aided drug design, translational drug informatics and semantic integration, with the goal of better synergizing experimental and in-silico approaches for developing small molecule tool compounds and drug leads. For the IDG grant, his research will focus on four of the most commonly drug-targeted protein families – G-protein-coupled receptors (GPCRs), kinases, ion channels and nuclear hormone receptors.

Biological systems contain only four types of adaptable macromolecule — proteins, polysaccharides, lipids and nucleic acids. Toxicity, specificity and the inability to obtain efficacious compounds against the latter three indicate that the vast majority of successful drugs achieve their effectiveness by binding to and modifying the activity of a protein. This limits the molecular targets for which commercially viable compounds can be developed, leading to the concept of the druggable genome.

According to the NIH, by expanding the scope of the potential druggable genome through further understanding of the properties and functions of proteins for which there are currently no known chemical probes, the therapeutics discovery pipeline can be energized and new scientific pathways for understanding their roles in disease revealed.

Schürer also is principal investigator of the NIH-funded Library of Integrated Network-Based Cellular Signatures (LINCS), which focuses on systems biology to better understand and model diseases, particularly cancer, and healthy cell states.

Pooling resources from LINCS, Schürer and his team are combining big data computational systems biology and cheminformatics and computational chemistry approaches to systematically analyze and compare drug target binding sites among protein families across the druggable proteome, the set of proteins expressed by a genome, to identify proteins that can potentially be targeted together.

In one example, Schürer says his lab is developing novel polypharmacology compounds targeting human kinases and epigenetic reader domain (bromodomain) containing proteins with the goal of overcoming resistance that frequently occurs in the current kinase inhibitor cancer drugs and represents a major therapeutic hurdle.

“Drug discovery efforts will increasingly focus on network poly-pharmacology approaches,” Schürer said, describing a biological system as a robust network of protein nodes and their connections, similar to the Internet. “If a node or connection is interrupted or slows down, there are ways the system can balance and counteract this perturbation with minimum consequences for end users (i.e. phenotypes).”

“This is one way resistance emerges in cancer,” Schürer explains, “so the strategy is to target combinations of nodes to achieve a desired effect, while leaving others undisturbed to avoid side effects.”

“This is what IDG is about,” Schürer said. “How we can accelerate the development of compounds for novel drug targets and beyond that, poly-pharmacology drugs that target complex disease at multiple points in the network.”

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