Drug Discovery Accelerated

By Jonathan Bohmann

The search for solutions to human suffering dates back to the beginnings of civilization. The earliest treatments were typically based on observations of nature and superstitions, consisting largely of some combination of ritual and plant- or animal-based ingredients. Modern drug discovery began in the 1800s, when scientists began to isolate compounds from natural sources to create the first drugs. The 1900s saw advancements in synthetic chemistry, antibiotics and an understanding of drug mechanics.

In the early 2000s, the onerous drug discovery process developed in the 20th century remained largely unchanged. While scientists no longer manually screened thousands of compounds in search of viable drug candidates, high-throughput screening methods developed in the 1990s only automated screening for a few hundred to a few thousand compounds at a time.

Developing viable candidates into a clinical drug remained a 10- to 15-year endeavor. For context, Alexander Fleming’s 1928 discovery of penicillin did not start saving patient lives until the 1940s. The cancer-fighting drug Keytruda®, developed in the early part of the 21st century, took about as long to arrive on pharmacy shelves in 2014.

Around 2010, Southwest Research Institute tapped its multidisciplinary expertise in computer science and chemistry to develop a rudimentary version of Rhodium™, SwRI’s proprietary molecular docking platform.

This Rhodium image shows how various small-molecule keys bind with a large, disease-causing molecule, allowing chemists to assess the best drug candidates for halting or treating infections.

A grandfather clock offers an apt analogy for drug discovery that connects the contexts for antivirals or cancer therapeutics. The clock represents a large disease-causing molecule such as a protein produced by a virus or tumor needed to spread or grow. The protein requires special keys, or small molecules, that fit precisely into a keyhole or binding site to cause undesirable replication. For a clock, the key winds the mechanism that keeps it running. Viruses or invasive tumors will spread or grow unless the replicating agent is locked out. In the context of antivirals, drug developers look for “inhibitor” keys or ways to stop the “clock” and thwart infected cells. These inhibitors may compare to tipping the clock over, jamming its hands or filling in the keyhole. Rhodium identifies inhibitors to stop the clock and ranks how well those small molecules will perform against viruses or, for oncology, address rapid, uncontrolled cell growth.

Rhodium software enables computer-aided drug design and structure-based virtual screening to accelerate drug discovery and allow for strategic development of pharmaceuticals.

Molecular docking uses computational methods to predict the preferred orientation of one molecule to another, like a ligand binding to a protein. It essentially predicts how a small molecule, the ligand, will meld with the binding site of a larger molecule, the protein, similar to a lock and key.

Scientists began using Rhodium for SwRI’s medical countermeasures research to speed up the search for viable antidotes for nerve agents and pesticide exposure. With Rhodium, picking winning compounds was no longer a lengthy process of elimination nor a matter of chance. The initial code for Rhodium provided a springboard for further development.

In 2013, chemists used Rhodium software to screen potential treatments for Alzheimer’s disease (red), shown here interacting with a neural enzyme (cyan).

RHODIUM EDGE

Rhodium pinpoints and predicts precisely where a drug will likely bind to a protein associated with a disease based on its 3D structure. When a drug molecule binds with a protein, it can block or modify the functionality of the protein to circumvent disease.

SwRI’s pharmaceutical and bioengineering researchers support every facet of drug discovery and development through clinical trials, following Current Good Manufacturing Practices. Rhodium molecular docking services supercharge what’s possible for clients, allowing comprehensive 3D analysis of the protein crystal structure of target molecules, such as proteins key to diseases. It is particularly advantageous during the initial drug discovery phase, because conducting early screening for new medications is expensive, time consuming, and may be limited by specialized lab access, such as biosafety constraints in discovery of new anti-infective drugs. Eventually new drugs are tested in clinical trials. But first, meeting strict potency and purity standards is required for obtaining FDA approval for a trial.

Rhodium can narrow down the list of potential treatments for disease, scouring massive in silico compound libraries for those with a high probability of effectiveness or potency, using fully traceable simulations. SwRI offers small molecule protein docking simulations as a service to SwRI clients and collaborators to support their drug development programs.

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ABOUT THE AUTHOR

Dr. Jonathan Bohmann is a staff scientist who pioneered the development of SwRI’s high-performance Rhodium molecular docking platform. This novel simulation program has proven applications in diverse areas of drug discovery, including neuroscience, virology, oncology and anti-infectives. Bohmann presented a poster about research into henipavirus countermeasures at the Hendra@30 conference sponsored by Australia’s National Science Agency CSIRO. Bohmann co-authored the work with Dr. Stanton McHardy of The University of Texas at San Antonio and Dr. Olena Shtanko of Texas Biomedical Research Institute.