South Ural State University researchers are working on solving global issues of science and technology, and their developments, without any exaggeration, could become breakthroughs for all of humanity. Maria Aleksandrovna Grishina, Doctor of Sciences (Chemistry), head researcher of the Computer Simulation of Medications laboratory of the SUSU School of Medical Biology.
“Together with the Head of our Laboratory, Candidate of Sciences (Chemistry) Vladimir Aleksandrovich Potyomkin we have been working on solutions of several tasks for more than twenty years now,” says the researcher. “The first of the most important of them is the creation of new medications with minimal negative effects and low toxicity. The second one is related to the development of the so-called photosensitive dyes, sensitizers, for solar batteries.”
“Work in the first field is related to diagnosing more than 50 kinds of biological activity using our own special methods. This includes research related to searching for anti-tumor, anti-inflammatory, and anti-viral solutions, including medication for HIV, flue, and so on. We also simulate vasorelaxants, which are used in treating hypertension and illnesses of the cardiovascular system. We are working on anti-bacterial solutions, including those for tuberculosis, and medications for staphylococcus, e-coli, and other disease-causing microorganisms.
Work on searching for anti-cancer solutions is related directly to the study of the DNA of tumor cells. This allows us to create medications which are able to face the third or even fourth stages of cancer.”
How the Work Is Structured
“We predict the efficacy of medications virtually, using powerful computers,” continues Maria Aleksandrovna. “We are looking for a formula of a substance which is effective for treating a particular illness. Then we need to synthesize it. For this, we pass the structure of promising compounds on to our chemists. They synthesize this compound and send it off for biological testing. We work in this way with University of Catania (Italy), University of Tubingen (German), and Aristotle University of Thessaloniki (Greece). It is encouraging that a number of medications which we have synthesized, especially anti-cancer and anti-inflammatory ones, showed high biological activity in testing.
Research is carried out using unique software which we developed ourselves. The methods and approaches that we have developed make it possible to model the interaction of medications with components of the biological system, for example, with the DNA of cancer cells or with one of the most important enzymes – dihydrofolate reductase, topoisomerase types 1 and 2, and so on. By blocking this DNA or these enzymes, we can remove cancer cells’ ability to grow and reproduce. The issue is that cancer cells are very similar to the cells of their host, and we need to make sure that the medication works specifically with cancerous cells and minimally affects healthy cells; that is, it must be minimally toxic. This is a very important field of research: quite a number of anti-cancer medications have been created, but many of them have side effects – they affect heart negatively, for example. And after all, the goal of treatment is to make people healthy and allow them to live full life.
We have found formulas for two anti-cancer and two anti-inflammatory medications which, by our forecasts, should be effective. They have been synthesized and have undergone initial biological testing, showing high efficacy. More detailed research of these compounds is now necessary, first on animals, including primates. The compounds can only be passed on for clinical testing, that is, testing on volunteers, if they successfully pass testing on primates.
Typically, around 10-15 years of work goes in to developing new medications worldwide. We pass on our information to our international colleagues virtually – not medications, but formulas, which are unfortunately impossible to patent. It is only possible to patent completed compounds. Nonetheless, this kind of partnership with international specialists was necessary to make sure that we are correctly simulating processes and predicting biological activity. This is what we need testing for.”
“About a year ago, Vladimir Aleksandrovich Potyomkin and I began working on a topic which is new for us but is very promising – development of special sensitizers which absorb light; dyes for solar batteries,” says Maria Aleksandrovna. “Many current sensitizers include cyano group, which can increase their ecotoxicity. We are looking for a chemical structure for these dyes for them to be used effectively but not adversely affect neither human health nor health of the surrounding environment.”
Human Resources and More
“Our laboratory does not have large staff – just five people,” continues the researcher. “Besides us, we also have senior laboratory assistant Maria Sergeevna Trunina and engineers Nadezhda Nikolaevna Palko and Maria Viktorovna Vasilieva. The university is inviting young specialists from the Republic of South Africa and Croatia, and Nigeria is also interested.
Such theoretical research is in high demand abroad. Especially in all universities of the Western Europe and USA which deal with development of medications, and solar batteries. The articles written by Vladimir Aleksandrovich Potyomkin and me are quite often cited by our foreign colleagues. Among these publications are: “A new paradigm for pattern recognition of drugs” issued in 2008 in Journal of Computer Aided Molecular Design; “Principles for 3D/4D QSAR classification of drugs” published in the same year in Drug discovery today, and “Technique for Energy Decomposition in the Study of “Receptor-Ligand” Complexes released in 2009 in Journal of Chemical Information and Modeling. In addition, our article “Online chemical modeling environment (OCHEM): web platform for data storage, model development and publishing of chemical information”, which was released in the Journal of Computer Aided Molecular Design in 2011 and written in cooperation with international colleagues, is also often cited.
We get actively published in highly-rated journals and participate in international conferences on the relevant theme. For example, not so long ago we took part in the Green and Sustainable Chemistry Conference held in Berlin and the Drug Discovery and Therapy World Congress which was held in Boston (Massachusetts, USA). These kinds of trips are extremely helpful for making new business and research contacts. For example, not so long ago, we formed a BRICS grant application with Indian colleagues from the University of Delhi, who we met at the congress in Boston. Researchers from four countries are creating a consortium for developing new medications. Russia will be completing the theoretical research. India is working on the medication synthesis and, together with Brazil, on biological testing. The RSA will also be working on theoretical and experimental research.”
We Can Do It Ourselves?
“Of course, we would like it if not only the theoretical research but also the creation and testing of medications would all be done in Russia. Our country can and should be a leader in pharmaceuticals. We need for new medications to be helpful for individuals and profitable for the country. Right now, on average, the development of medication abroad costs around 350-500 million dollars, or even more. This is because much testing is done “blindly”, using random compounds. With our developments, we can significantly decrease the costs of testing by only completing them with compounds which are predicted to be successful.
Yes, the creation of medications is very expensive, but the costs pay off in just a couple years if the efficacy of the medication is proven. Modern medications are effective in very small doses. In many cases, it is enough to synthesize a handful of substances that have a therapeutic effect to help all of the people on the planet with a particular disease. But significant funds must be invested. Much of what existed in the USSR is necessary to recreate – laboratories and research centers need to be rebuilt.
To not be dependent upon international partners, we must develop Russian pharmaceutical industry; we need well-equipped laboratories for the synthesis and testing of medications on the necessary level. But serious research is expensive. For example, the cost of one primate and its housing can be up to a few tens and sometimes hundreds of thousands of US dollars. And we need special primates from a full-blooded line. Of course, everything must be done legally. In the Soviet times, primates were raised in the famous Sukhumi monkey colony. It exists now, but it was seriously damaged in the Georgian-Abkhazian war. At the clinical testing stage, we also need significant resources, including financial ones. For example, in the USA, pharmaceutical companies pay volunteers for participation in testing candidate medications which have been previously tested on animals.
I’ll stress again: the qualifications of Russian researchers, including those from the SUSU SMB, make it possible to complete research on a very high level. Medications created from such studies will have and now have high efficacy with minimal negative side effects. Russia can become a leader in pharmaceutical manufacturing and create competitive medications.”
“Only one in a million molecules becomes medication. But this is a very interesting topic,” says the researcher. “Imagine, using our methods you could find this molecule among many others and complete only its synthesis and biological testing without wasting neither time nor money on the other, unpromising compounds. In this way, for example, we could find a medication formulation for tuberculosis. We are looking for medications using computers, and the predictive value of these models is very high. The process of biological action is simulated very accurately and professionally, examining the structure of the chemical compounds in all of their forms, taking into account the adjustment of geometry of the molecules to their environment or the form of the receptor, for example, in a cavity in a DNA molecule or in an enzyme. A molecule of an enzyme, and more so a cell, can be ten times larger than a medication molecule. The drug molecule must penetrate the cell and effectively interact with the receptor. However, it sometimes occurs that the medication interacts with the P450 cytochromes and takes part in the metabolic process. During metabolism, destruction occurs, that is, the molecule can be destroyed. As a result, the therapeutic effects of the medication are lost and negative side effects occur, and the medication can even turn in to a kind of poison. But pharmacologists can use metabolism to their advantage: they can create a prodrug, so that a substance which gives the therapeutic effect is released as a result of the metabolic process. A good example of this is the well-known aspirin or acetylsalicylic acid: under the affects of metabolism, salicylic acid is released from it, which has a therapeutic effect. It is therefore necessary to carefully calculate how a substance behaves once it enters human body.”
“I would like to thank with all my heart the leadership of SUSU, and personally the Rector Alexander Leonidovich Shestakov, for the chance to participate in international forums and be published in highly-rated international journals: this encourages me morally and financially. Also, thanks to the help of the rectorate, we have gained very good computers which allow us to complete difficult research on the protein structures and interactions of medications with proteins and study nanoparticles, crystal fragments, and large molecular systems. Access to the international database for x-ray diffraction analyses of targets was opened for researchers. There, we can obtain information on the structures of protein molecules. Using our computers, we imitate their interactions with candidate medications and calculate the reaction of biotargets (DNA, RNA, proteins, enzymes, and other substances in body) to these medications.
It is well known that for researchers to work here in Russia, relevant conditions must be created. For the development of Russian pharmacology, we need to invite international specialists, buy equipment and animals for testing, and also purchase chemical and biological materials. We need for our specialists to be able to realize their scientific potential, not work on unnecessary things. For this, we need a good industrial base which is able to produce competitive products. Our country has the potential to create high-quality medicines which will be cheaper than international medications. But besides funds, we also need the willingness of business, the government, and the industry. Then our specialists will not leave the country, and we will be successful.”