The entire process of creation of a new medicinal compound in a number of cases can be divided into following stages:
- Search for the aim (such as protide) for the new medicine;
- Search for a low-molecular compound having the required pharmacological effect;
- Experimental examination of the compound;
- Carrying out the clinical experiments.
Only a small percent of the potential medicines passes the clinical test successfully. In general, creating a single medicine takes from 1 to 2.5 billion dollars and about 10–15 years.
The essence of the medicine — that is, the thing which helps a person to recover, is in its active agent. In combination with various chemical additives, it can become, for instance, a colorful pill suit to be swallowed. Speaking of medicines, further we will refer to their active agents.
There are many chemical processes taking place in the human body. They can be described by the reaction cascades (Fig.1), which can be quite large and complex. The development of a disease is accompanied by the disruptions of some of the organism’s processes. The reaction cascades have key participants (some molecules mostly protides), which are generally responsible for everything taking place. It is for them the medicines are developed, that is, the medicines are aimed at these molecules.
However protides are big molecules. That is why it’s not enough to simply calculate the protide as the target among the cascades and networks; it is required to determine a specific place on that target. This place is called the active site. Interaction of the right medicine with this very place is what gives the desired effect — health improvement and recovery.
Imagine a key and a lock. Interaction of the medicine with the target protide is the same as using the key to unlock the lock. To interact with the necessary center of the protide, the medicinal molecule has to meet various physical, chemical and even geometrical requirements. The lock should match the key. So, the molecule which has medicinal activity suitable against a specific disease, ties itself with the active site of the target protide, which modulates its activity (Fig.2). Very often this modulating consists of inhibition (suppressing) of its interaction with other molecules. In such a manner, the errors are corrected and the disease is cured. Although it is important to underline the fact that molecular mechanisms by which the medicines influence the targets and further perform changes in reaction cascades are various and complex.
If space structure of the target protide is known, then the first thing to do is to is to determine the place of tying of the low-molecular compound (medicine) to the target protide. After that, the resulting complex is analyzed using molecular graphics (so called docking) with following molecular-dynamic and quantum chemical estimation. The very first stage of the search for the potential medicine is related to enumeration of hundreds of millions of variants from the respective data base of the low-molecular compounds.
In case when the space structure of the target protide is unknown, there is quite a large number of various approaches of comparative modelling. While creating a 3D model of the protide with predetermined amino acid sequence this polypeptide chain at first “writes” itself into the coordinates corresponding the remains of the homological protide with the deciphered space structure, and then the inner energy is minimized to “remove” possible tensions in the structure. Further, with the methods of molecular dynamics, the movement of separate parts of the molecule is modeled to specify the position of flexible parts. The quality of the resulting model is evaluated using the program which compares spatial location of the amino acid remains of the protide being modeled with known statistics, gained for the protides with the space structure deciphered experimentally.
The models created this way were successfully used in designing, for instance: of new inhibitors of the HIV protease for AIDS curing; of inhibitors of renin as means for curing essential hypertension; for protein engineering of hybrid neutroforn factors etc. The Elige.re project is aimed at helping to find new medicine, protides and other chemical compounds.
Any sound conclusion can be made only if we would know all the genes and protides in our organism. Previously, to receive such data special experiments were carried out but imagine: average bacterium has approximately 3000 genes, humans have much more — 30 000 genes the number of protides is even more — so how many experiments should be made for, instance, to check all the protide pairs on interaction. Furthermore, most of the time will be wasted on “vain” experiments studying non interacting protides. The same goes for the gene functions. Technically, finding out the function of a single gene experimentally would take a year worth of work of an effective researcher and a good article. But in our organisms there are thousands of genes.
All the stages of such researches require high-performance computations.
To solve such resource-intensive and complex computation problems high-performance computing systems are used, including supercomputers and computer clusters and grid computing.
However, this is the matter of discussion for our next article.
Olesya Untevskaya, exclusively for the Elige.re project
In Russian: Создание лекарственных средств
