The medicine will hit exactly the target
Neural news
Researchers from MIPT and a number of institutes in the USA and China have managed to decipher the structure of one of the most important proteins of the nervous system in combination with several drug molecules. This work opens up opportunities for the development of new drugs with controlled action and reduced side effects. The study is published in the journal Cell (Peng et al., 5-HT 2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology).
"Magic Bullet" vs. "magic Shotgun"
Many modern medicines act on proteins. This is due to the fact that it is protein molecules that do most of the physical and chemical work in the cell, are receivers and transmitters of information between cells, and so on. In case of illness, the well-coordinated work of proteins is disrupted, and the medicine allows you to restore balance, temporarily slowing down or strengthening their work. Many proteins that perform a similar function are often arranged almost identically, and the same drug molecule can act on several of their types. The ability of a drug to interact with several types of proteins is called polypharmacology.
At the dawn of the molecular era in drug development, the prevailing opinion among scientists was that the effectiveness of the drug was provided by exposure to one specific type of proteins in the body. Exposure to all other types causes only side effects that doctors have to deal with. Therefore, the main task of all pharmacology at that time was to give new medicinal substances maximum selectivity – the ability to act only on one type of protein. This concept is anchored by the successful metaphor of Nobel laureate Paul Ehrlich, who called highly selective drugs a "magic bullet".
However, as often happens in science, the simplest concept was not necessarily the most successful. The development of computer technologies in chemistry and biology made it possible to obtain very selective drugs limited to only 2-3 close subtypes of the target protein, but their effectiveness in the case of some complex diseases like depression decreased sharply compared to low-selective analogues. The polypharmacology of some drugs turned out to be an important component of their action. It does not necessarily have to cause serious side effects, but it is necessary to subtly control which proteins the drug acts on. The "magic bullet" was replaced by the "magic shotgun" – a medicine that acts properly on the right set of targets.
Attachment points
The task of researchers from MIPT and their foreign colleagues was to identify the structural features of proteins, due to which some drugs act selectively on them, while others do not. Serotonin receptor 5-HT 2c, a signaling protein located in the cell membrane and receiving a signal from neighbors with the help of the hormone serotonin, was chosen for the work. It has a number of important features. Firstly, this receptor is already an important target in the treatment of obesity and, potentially, a number of mental illnesses. Secondly, there are many drugs for it with very different selectivity that can be compared with each other. Thirdly, there are about 800 more receptors in the human body that are vaguely similar in structure to 5-HT 2c (they belong to the class of semispiral receptors or GPCR), but perform different functions, so non-selective drugs to it often cause an impressive bouquet of various adverse reactions.
Vsevolod Katrich, a visiting professor at MIPT, explains: "To work with the serotonin receptor 5HT 2c, 2 drugs were used: ergotamine and ritanserin. Ergotamine is a non–selective agonist that has a broad polypharmacological profile, acting on serotonin, dopamine and adrenergic receptors. Ritanserin, on the contrary, has a narrower polypharmacological profile and is a selective reverse agonist to the serotonin receptor 5HT 2c. Thus, the atomic structures of 5HT 2c obtained in complexes with ergotamine and ritanserin make it possible not only to understand how the active and inactive states of the receptor differ (which in itself is a high achievement), but also to establish the reasons for the selectivity of these molecules."
Comparison of the selectivity of the studied drugs ergotamine and ritanserin. The most important difference between them is the selectivity profile, that is, the set of body proteins with which they can interact. Ritanserin is an extremely selective drug that acts only on certain subtypes of the serotonin receptor (dark blue–a circle with yellow circles). Ergotamine affects not only all targets of ritanserin (the blue circle, which includes dark blue), but also more than 800 other proteins of the body, causing many diverse effects. Designer – Elena Khavina, MIPT press service.
Using X-ray crystallography, the researchers obtained a 3D model of the protein at the time of interaction with the drug. As expected, the binding of drugs to the receptor occurs in different ways. The region to which ergotamine binds is arranged very similarly in many proteins, which ensures its non-selectivity. Ritanserin binds to the receptor in a slightly different way and interacts with certain fragments unique to the small group of proteins on which it acts. Scientists have confirmed that these protein regions are responsible for selectivity by introducing several mutations into the 5HT 2c receptor gene that alter these fragments. In all cases, this led to a decrease in the strength of interaction with ritanserin.
Peter Popov, an employee of the Laboratory of Structural Biology of G-protein coupled receptors, MIPT says: "The main difficulty in determining the structure of these receptors was to obtain a stable genetically engineered structure that is suitable for crystallization and further study. Using a bioinformatic approach using machine learning methods, we have identified stabilizing point mutations for the 5HT 2c receptor in both the active and inactive states."
Medications attach to proteins in different ways. X-ray images of protein complexes with drugs obtained by the researchers made it possible to study the differences in the way the drug molecule is fixed on the protein surface. As you can see, ergotamine (orange molecule) is located on the surface of the protein in a completely different way than ritanserin (green molecule). In addition, they interact with different amino acids in the target molecule, which explains the greater selectivity of ritanserin in comparison with ergotamine. Source: Yao Peng et al., Cell.
Thus, the analysis of the structural features of the protein in combination with drugs of different selectivity has shown its effectiveness: with its help, we will be able to control a set of targets, which means direct and side effects of drugs at the development stage. Thanks to this, patients will be able to receive more effective therapy for many diseases with fewer side effects.
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