Drug design in 3D

By Heather Buschman, Ph.D.
October 5, 2010
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Let’s say you are a scientist studying Protein X, a protein that normally tells cells to divide but, when malfunctioning,  causes unchecked cell division that leads to a tumor. You think blocking this deviant Protein X might stop cancer. So you take Protein X to your colleagues in Sanford-Burnham’s Conrad Prebys Center for Chemical Genomics (Prebys Center), where robotic systems can screen hundreds of thousands  of chemical compounds to find that one needle-in-a-haystack (or handful of needles) that inhibit Protein X. From there, you continue developing these winning compounds, hopefully into a new anti-cancer drug.

To boost the Prebys Center’s drug discovery efforts,  scientists in Dr. Nicholas Cosford’s laboratory, part of Sanford-Burnham Cancer Center’s Apoptosis and Cell Death Program, are putting on their 3D glasses. They recently teamed up with French company MEDIT SA to use and enhance a new software platform built around a computer program called MED-SuMo. This platform breaks down 3D images of known protein structures to find chemical fragments that might bind and inhibit Protein X (or other interesting proteins) in real life.

“We believe that this collaboration with MEDIT significantly enhances our ability to perform structure-based drug design,” says Dr. Cosford, associate professor and leader of the collaborative team. “MEDIT’s MED-SuMo software offers unique capabilities that will complement drug discovery platforms already underway in the Prebys Center.”

Here’s how it works. MED-SuMo takes a 3D model of Protein X and breaks it down into pieces. Then the software digs through a publically available database containing more than 60,000 proteins with known structures to find “hits” – pieces that structurally resemble parts of Protein X, but are already known to bind certain compounds. MED-SuMo superimposes the matching hits on the structure of Protein X, allowing researchers to see a 3D image of the interaction. Chemical fragments bound to the hits will bind to Protein X in a similar fashion, forming the initial building blocks for a new drug.

“We’re using MEDIT’s software to look for highly effective drugs,” explains Peter Teriete, Ph.D., a post-doctoral researcher in Dr. Cosford’s group. “The great thing about using MED-SuMo at Sanford-Burnham is that we’re also surrounded by drug discovery experts. So if I find something that looks good on the computer, I can work with chemists and assay developers to synthesize the compound in the lab and test it to determine whether or not it has the potential to become a new drug.”

Once MED-SuMo puts these pieces together, MEDIT technology takes drug design several steps further. Another program, called MED-Ligand, can optimize multiple hits by finding ways they could be combined to form a single hybrid drug compound that binds Protein X better and more selectively. The system can even screen out any combinations that couldn’t realistically be generated by chemists in the laboratory, as well as those that might harm other proteins or cause toxicity in humans.

The collaboration goes both ways –  Dr. Teriete and others benefit from the software and MEDIT SA’s engineers benefit from their feedback on what works, what could work better and what additional features would be helpful. Their ideas and experiences will improve future versions of MEDIT’s technology platform, making it an even more powerful tool for drug discovery.

“As structural biologists, we are excited about this new technology because it helps us to further translate our latest findings into the development of new therapies,” says Dr. Stefan Riedl, assistant professor at Sanford-Burnham and another new MED-SuMo user.

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Heather Buschman, Ph.D.

Heather was an SBP Communications staff member.

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