VCU news

By Dina Weinstein

Considering what was on his plate this fall, Samuel Holmes had to be a model of efficiency. He led a research seminar in mid-October, defended his dissertation a few days later, started his postdoctoral work in in Georgia in November and returned to Richmond this month for graduation.

But models – of a different sort – are his specialty. In earning his doctorate in medicinal chemistry at Virginia Commonwealth University’s School of Pharmacy, Holmes used computational modeling to explore nanoscale frontiers that, when enhanced, could help guide therapies for cancer. His doctoral research focused on heparin, the body’s well-known blood thinner whose unusual structural properties could play a role in treatment.

Heparin is a polysaccharide, a long and linear chain of sugars that is so tiny it’s on the angstrom level. “It’s a lot easier to build computational models for heparin than it is to actually get that sequence in real life,” Holmes said from his postdoc research lab at the University of Georgia.

The native of Mechanicsville in Hanover County nurtured his interest in medicinal chemistry as an undergraduate at James Madison University. The chemistry major got involved in biochemical research and attempted to purify an enzyme.

“In my undergrad lab, I was first exposed to molecular dynamics computer simulation,” Holmes said. “It’s very visual, where you can actually watch a protein move around in a biological environment on the screen and you can see how it would interact in the cell if it was surrounded by water and ions and all that other stuff. I thought it was just really fascinating because it was almost like a video game, but it was science.”

At VCU, working in the lab of professor and department chair Umesh Desai, Ph.D., Holmes found a setting and advisor that combined his interest in medicinal chemistry and its connection to molecular modeling and dynamics. Desai described his protégé’s work as “very fundamental, but it has applications in therapeutics as well.”

Heparin is an extremely difficult polysaccharide to study, Holmes said. “It’s very hard to get a pure sample of anything that you would want to test experimentally. So, an alternative to that is to build 3D models via a computer.”

As a chain of sugars, heparin adopts a very extended linear shape. Applying computer simulations to a library of heparin polysaccharides, Holmes tracked structural changes that occur when a sulfate is installed at specific positions on certain chains.

“They’ll actually fold on top of themselves and form a C shape, which was really unusual and not something that had ever been documented before in the heparin field,” he said. “If you can identify certain heparin sequences that are not linear, that makes them interesting and rare – and also likely means that they are very, very selective for a specific protein.”

The implication is significant for potential cancer treatment, Holmes said.

“If we can also experimentally show that this shape change actually occurs, then medicinal chemists in the future can design molecules that will mimic this new key shape, which will then allow for a very selective drug to bind to a very selective protein,” he said.

As with cancer, glycosidic glycans such as heparin play a role in heart attack, stroke and inflammatory conditions. In his postdoc work at the University of Georgia, Holmes is building 3D computational models for heparin on a large and complex server called GLYCAM-Web, which he used during his Ph.D. research at VCU.

“GLYCAM-Web allows any glycobiologist around the world to build a 3D model of whatever glycan that they’re interested in,” Holmes said. So now, his work will have a larger reach than ever, making the promising data available for scientists anywhere to analyze and pursue.