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- The connecting link: scientists have accelerated the search for effective cancer drugs
The connecting link: scientists have accelerated the search for effective cancer drugs
Russian scientists have created a combined method for searching for protein binding sites with drugs used in cancer treatment. The technology is suitable for phototherapy, in which malignant tumors are affected by photosensitive compounds and are affected by radiation of a certain wavelength. The new method will make it possible to select drugs that are better distributed throughout the body and more actively concentrated in tumor cells. Experts believe that this approach will be in demand in practice and will make the drug development process faster, more predictable and manageable. In the future, this will accelerate the emergence of more effective and safer drugs.
What is photodynamic cancer therapy?
Scientists from Novosibirsk State University, the International Tomographic Center of the Siberian Branch of the Russian Academy of Sciences and the staff of RTU MIREA have developed a method that will allow the most effective selection of a drug in the process of photodynamic oncotherapy. This is a treatment method based on the use of photosensitive substances (photosensitizers) and light of a certain wavelength. It is used, among other things, to combat malignant tumors and precancerous conditions, the press service of the Ministry of Education and Science reported.
When drugs enter the human body, they primarily interact with proteins contained in the blood. How effective a particular drug is depends on the degree of its binding to serum albumin, a protein responsible for the transport of substances in the body and contained in blood plasma. If the binding is too strong, the concentration of the drug in the blood will be reduced, and if weak, it may be unevenly distributed in the body or completely destroyed before reaching the desired goal.
— In order to create an effective drug and control its binding to the transport protein, it is important to know which site its molecules will attach to. The identification of such sites will lead to an understanding of the mechanism of action of drugs, prediction of side effects and identification of the causes of resistance to it in some patients," Mikhail Kolokolov, a junior researcher at the Laboratory of Electronic Paramagnetic Resonance of the International Tomographic Center, told Izvestia.
Scientists have proposed their own combined approach that allows measuring the distance between different elements of the complex and using them to obtain its structure. Previously applied methods produce average values, in this case it is possible to achieve atomic accuracy in measuring the distribution of distances between binding sites and "see" all possible conformations, that is, the spatial arrangements of atoms in a molecule of a certain configuration, and find places where small molecules of a substance interact with a protein.
— In our approach, we measure the distances inside the complex using spin tags. A special small molecule containing an unpaired spin is selectively introduced into the protein region known to us. After it binds to the drug, we can measure the distances between the spin label and the drug molecules," Mikhail Kolokolov explained.
In their approach, the scientists combined molecular modeling methods with experimental data obtained by the electron paramagnetic resonance (EPR) method, which makes it possible to determine the structure of compounds based on information about how they absorb microwave radiation.
The scientists tested their combined approach by investigating the binding of albumin to photosensitizers.
Photosensitizers are natural or synthetic substances that are used in medicine, for example in photodynamic therapy (PDT), where they accumulate in pathological cells and are activated when exposed to light, causing their death.
Cancer drug Development
The new approach has shown that binding can be carried out in non-standard albumin sites and in several sites simultaneously for different types of these substances.
— In the course of all our experiments, we have shown with atomic precision where the molecules of these compounds bind to albumin, which is a novelty from the point of view of developing photosensitizers. Our combined approach will make the analysis of anti—cancer compounds much more accurate, and the process of developing new drugs for cancer therapy easier and faster. Now we are going to apply the approach we have developed to study how photosensitizers bind to DNA molecules," said Mikhail Kolokolov.
Thanks to the combination of computer analysis and electronic paramagnetic resonance data, the scientists were able to significantly reduce the number of time-consuming calculations and experiments, simplify the determination of interactions between albumin and photosensitizers. This work will make it possible to predict the most promising compounds for photodynamic anticancer therapy.
A method that visualizes drug binding to albumin may open a new page in the design of anticancer drugs. It allows you to create molecules not blindly, but purposefully, ensuring their optimal distribution in the body and minimizing side effects, explained Andrey Burkov, Director of Strategic Marketing and Product Portfolio Development at R-Pharm.
"Integrating this test into standard preclinical screening is, in fact, an additional control step that reduces risks in studies involving patients and volunteers. This makes the entire development process faster, more predictable and manageable, which in the future will accelerate the emergence of more effective and safe drugs," the specialist told Izvestia.
The developed method makes it possible to determine exactly how photosensitizers, substances used in photodynamic therapy, interact with body proteins, added molecular biologist Arina Kholkina.
Photosensitizers accumulate in tumor cells and, when exposed to light, destroy them without damaging healthy tissues. The effectiveness of treatment directly depends on how well these molecules bind to blood proteins and reach the tumor. A new combined approach combining EPR spectroscopy data and computer modeling makes it possible to determine the sites of such binding with high accuracy. This helps to quickly select photosensitizers that are better distributed throughout the body and more actively concentrated in tumor cells," she said.
According to her, the development makes the search and creation of drugs for PDT more accurate, safe and effective, paving the way for improved methods of targeted cancer therapy.
The results of the study are published in the Journal of the American Chemical Society.
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