Cystenyl-leukotriene receptors
Scientists deactivated oncogenic mutant
Natalia Safronova, "Scientific Russia"
Structural biologists from MIPT together with colleagues from the USA conducted two complementary studies of cystenyl-leukotriene receptors, both works were published in highly rated scientific publications (Nature Scientific Data and Biomolecules). The results of these studies are of great interest to medicine. The chemical compounds found by the virtual screening method can become new medicines for asthma and rare cancers that have no analogues in the world.
Cystenyl-leukotriene receptors (CysLTR) are membrane proteins from the family of G-protein coupled receptors (G-protein-coupled receptors). In the human body, these receptors respond to endogenous cystenyl-leukotrienes – signaling substances involved in the development of inflammatory processes. Two types of CysLTR are known (CysLT1R and CysLT2R): they have about 40% sequence homology (to put it simply, 40% of their amino acids are the same) and slightly different specificity, but are expressed differently in the body. These receptors are involved in inflammatory reactions, in particular in the development of asthma, allergic rhinitis and cardiovascular diseases. Despite its clinical importance, few drugs are known to target these receptors (montelukast, zafirlukast, and others). Moreover, well-known drugs have insufficient effectiveness in severe cases, and also cause undesirable side effects. Biophysicists from MIPT made a significant contribution to the development of new drugs.
In the first article in the largest journal Nature Scientific Data (Marin et al., Small-wedge synchrotron and serial XFEL datasets for Cysteinyl leukotriene GPCRs), the authors published structural data for two cystenyl-leukotriene receptors obtained by serial synchrotron and serial femtosecond crystallography, and proposed methods for processing these data.
"Serial crystallography is an advanced method of modern structural biology. By collecting a diffraction pattern from a large number of crystals, this method makes it possible to obtain structural data of objects previously inaccessible to traditional crystallography – for example, human membrane proteins from the GPCR class. We hope that our work will make a significant contribution to the development of algorithms for advanced structural and biological methods," comments Valentin Borshchevsky, Deputy Head of the Laboratory for Advanced Research of Membrane Proteins at MIPT.
The second work (Sadybekov et al., Structure-Based Virtual Screening of Ultra-Large Library Yields Potential Antagonists for a Lipid GPCR) logically continues the first. Due to the presence of three-dimensional structures of two cystenyl-leukotriene receptors, it was possible to search for substances interacting with them.
In this paper, the authors, using three-dimensional computer models of CysLT1R and CysLT2R, conducted a virtual search for substances interacting with them. The search was carried out by molecular docking, while about 680 million possible chemical compounds were tested.
"Rational drug design is a modern method of drug development, which, according to various estimates, accelerates drug development by an average of 3 years and reduces its cost by 20-30 percent. Virtual screening using structures is a key method of the initial design stage. In our work, we have successfully used this method for CysLT receptors and found several potentially promising molecules, which, however, need further optimization if we want to use them in living organisms. It is important that we managed to find a molecule that "deactivates" the oncogenic mutant CysLT2R – it can potentially become a cure for uveal melanoma," says Alexey Mishin, deputy head of the Laboratory of Structural Biology of G protein coupled receptors, MIPT.
As a result, the authors found 155 compounds potentially interacting with these receptors. For 139 of them, the possibility of interaction with cystenyl-leukotriene receptors was tested experimentally. Of the studied compounds, 10 were able to significantly reduce the activity of CysLT1R and 17 – CysLT2R. Of these compounds, three of the most effective for each receptor were additionally tested by researchers. The key finding of the work was that the authors showed almost complete inhibition of the activity of the mutant form of CysLT2R (L129Q) by one of the compounds found. The activity of this receptor is associated with the development of uveal melanoma (a rare type of eye cancer). Thus, researchers from MIPT have found several promising compounds that can become the basis of a cure for uveal melanoma.
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