By using an innovative combination of chemical and computer analysis, researchers are one step closer to designing better cancer drugs.
Killing cells is not difficult. Killing cancer cells while leaving healthy cells intact, however, is another matter.
The hunt for anticancer drugs that specifically shut off enzymes that allow cancer cells to survive but do not cause havoc in healthy tissues is ongoing.
Researchers from Uppsala University and the Karolinska Institute in Stockholm, both in Sweden — along with colleagues at the University of Oxford in the United Kingdom — may have done just that by developing a new technique that shows how drugs inhibit the new cancer target dihydroorotate dehydrogenase (DHODH).
Michael Landreh, Ph.D. — an assistant professor in the Department of Microbiology, Tumor and Cell Biology at the Karolinska Institute — told Medical News Today about the team’s research.
“The possibility to selectively kill cancer cells while leaving healthy tissue unaffected was recently discovered by the lab of Sonia Lain [… at the] Karolinksa Institute who identified DHODH inhibitors in an unbiased screen […] for broad anticancer activity,” he said.
But studying which drugs effectively turn off membrane-bound proteins, such as DHODH, is technically very challenging. The team had to develop a new technique to overcome these difficulties.
Chemistry and computer simulation
DHODH is an enzyme located in the membranes of mitochondria, the cells’ powerhouses. Here, it is involved in the synthesis of new building blocks for DNA, the genetic code. This process is vital for cell division, and shutting it off has been shown to effectively kill breast cancer cells.
Using a chemical technique called native mass spectrometry allowed the research team to determine which molecules bind to DHODH.
Scientists often test new drug compounds on enzymes after they are isolated from cells. However, cell membranes contain a diverse array of lipids — or fat molecules — so Prof. Landreh and his colleagues studied DHODH in combination with lipids from mitochondria.
The team’s findings show that the potential cancer drug brequinar inhibits DHODH much more strongly in the presence of lipids.
“To our surprise, we saw that one drug seemed to bind better to the enzyme when lipid-like molecules were present,” says Prof. Landreh.
Next, Erik Marklund, Ph.D. — from the Department of Chemistry at Uppsala University — and his team used molecular dynamics simulations to show how these interactions between DHODH, lipids, and brequinar take place.
Drug mimics natural substrate
The coenzyme Q10 activates DHODH. Marklund’s analysis showed just how Q10 binds to DHODH: lipids are needed to stabilize the interaction between the two partners.
“Our simulations show that the enzyme uses a few lipids as anchors in the membrane. When binding to these lipids, a small part of the enzyme folds into an adapter that allows the enzyme to lift its natural substrate out of the membrane,” Marklund explains.
“It seems that the drug, since it binds in the same place, takes advantage of the same mechanism,” he adds.
In the paper, he further recommends that DHODH inhibitors should be designed to specifically capitalize on this interaction between the enzyme and lipids.
Commenting on the impact of the research, co-author Prof. Sir David Lane, from the Karolinska Institute, says, “The study helps to explain why some drugs bind differently to isolated proteins and proteins that are inside cells.”
“By studying the native structures and mechanisms for cancer targets, it may become possible to exploit their most distinct features to design new, more selective therapeutics.”
Prof. Sir David Lane
How does the team plan to use this discovery in the fight against cancer?
“The group now aims to exploit the specific membrane binding ability of DHODH to better tailor their inhibitors to allow more specific inhibition of the enzyme in cancer cells.” Prof. Landreh told MNT.
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