An employee of the National Research Nuclear University MEPhI, as part of an international scientific team, studied the anticancer effect of a drug for acute heart failure - istaroxime. The results were published in the highly rated scientific journal Molecules.
As you know, cancer cells actively divide, and their DNA replicates (doubling). To prepare for replication, the DNA molecule, which is a “braid” of two molecular chains, must “unravel” into two halves. This process is controlled by a special enzyme, topoisomerase. It “cuts” one (isomerase-I) or both (isomerase-II) strands of DNA, allowing them to free themselves from each other, and then “stitches” each of them back together.
Without topoisomerase, cell division is impossible, so many anticancer drugs are aimed specifically at it, explained co-author of the study, professor at the National Research Nuclear University MEPhI Konstantin Katin.
“The drug can not only suppress the activity of topoisomerase, but also turn it into poison: in this case, it still effectively breaks DNA chains, but is no longer able to stitch them together. As a result, the tumor, which always has an increased concentration of topoisomerases, stops growing. Of course, such drugs also have side effects - they interfere with the reproduction of normal cells. Therefore, scientists are looking for molecules with a satisfactory ratio between direct and side effects,” he said.
Researchers at the National Research Nuclear University MEPhI and their colleagues studied the istaroxime molecule and examined its activity in relation to lung, prostate and breast cancer. The studies were carried out ex vivo, that is, in tissues extracted from a living organism. It is believed that this approach makes it possible to almost perfectly reproduce the real characteristics of the human body, but at the same time better control the experimental conditions.
“According to the measurements, the concentration of the drug that doubled the proliferation of cancer cells was 12, 2 and 16 µmol/l, respectively, for the three types of cancer examined. In addition, we discovered a selective effect of the inhibitor on isomerase-I, while isomerase-II was affected to a lesser extent,” said Konstantin Katin.
To explain these results, the scientists supplemented the experimental studies with computer modeling of the docking process - the attachment of a drug to an enzyme.
“Topoisomerase is a huge molecule that has a small “Achilles heel” - a place that is vulnerable to attack by istaroxime. Modern methods of atomistic modeling make it possible to find this place, which often have to be enhanced by statistical analysis and machine learning,” explained the professor at the National Research Nuclear University MEPhI.
Understanding the mechanism of action of a drug at the molecular level will make it possible to purposefully create new and improve existing drugs. That is why computer modeling becomes the first step in the development of new drugs. It is planned that this direction will continue its development at NRNU MEPhI.
