Scientists are expected to develop new drug discovery strategies for "drug-free" drug targets

Membrane proteins play a very important role in biology, many of which are high-value drug targets that the pharmaceutical industry is digging into, and in this study, researchers Li et al. developed new methods that could provide an effective way to discover new membrane protein lids and inhibitors, but traditional methods still largely fail to address these issues.
proteins on the surface of cells have a variety of biological functions that are critical to the survival of cells and organisms.
Not surprisingly, many human diseases may be associated with abnormal membrane protein function, in fact, in the FDA approved small molecule drugs, membrane protein-targeted drugs accounted for more than 60%, only G protein conjunctivation (GPCR) super-family (the largest type of cell surface lithum), in all clinical drug targets accounted for 34% of the proportion.
However, despite its significance, the discovery of drugs for membrane proteins poses considerable challenges for scientists, largely depending on the properties of their natural "habitat", i.e. the characteristics of cell membranes;
In recent years, the advent of DNA-coded chemical libraries (DEL) has made it a very powerful drug screening technique, and to further simplify this, the researchers used the book library as an example, each book in the library has an index of directory numbers, and spatially encodes specific locations on shelves, similarly, in DEL, where each compound is attached to a unique DNA label to record the compound as a catalog number. Structural information; with DNA coding, compounds in all libraries can be mixed and screened simultaneously for targets to discover biological functions that regulate targets, such as special proteins that have been abnormally active in malignant cancers; DELs contain an alarming number of compounds to be tested (billions or even trillions), DEL screening can be performed in ordinary chemical laboratories in just a few hours; del is now widely used in almost all large pharmaceutical industries around the world. DEL has also encountered significant difficulties in "reviewing" membrane proteins on living cells.
For the use of DEL in living cells, researchers also need to overcome two obstacles, first, the cell surface is not like a balloon smooth convex structure, its topology is extremely complex, and contains hundreds of different biological molecules, so the cell surface positioning needs to target as if looking for a tree in a dense tropical forest, in this study, the researchers used previously developed methods (i.e., DNA programming affinity labeling technology, DPAL technology) to overcome this specific problem.
This approach uses a DNA-based probe system to specifically transport DNA tags to the proteins needed on living cells, and DNA tags can act as a beacon to guide targeted del screening, in other words, the researchers first installed a tracker on the target to achieve screening specificity.
The second challenge is the abundance of the target, where membrane proteins typically exist at concentrations from namol to low micromolars, far below the high micromolar concentrations needed to capture very small fractions of the billions of non-binding binds in the library; Using the DNA tag of the target protein and the complementary sequence in the actual library, the library can be close to the target protein hybridization, thereby increasing the effective concentration of the target protein, in other words, this tracker can not only help the library to locate the target, but also produce an attraction so that the library is concentrated around the target point, without interference from non-binding groups. In the
study, the researchers described in detail the development of their methods, and they also demonstrated the versatility and properties of these compounds by screening 30.42 million compound libraries on living cells for folic acid ligenase 12 (FR) carbonate enzyme 12 (CA-12) and skin growth factor (EGFR), and demonstrated the versatility and properties of this method, which are important targets for military cancer drugs.
could be widely used in many membrane proteins, such as classic drug targets such as GPCRs and ion channels, which could be re-examined in living cells and new drugs discovered by harnessing the power of DEL, the researchers said. 'We expect this approach to be more practical than just drug discovery, but also for exploring challenging biological systems, such as oligopolymer complexes and cell-cell-to-cell communication,' said
researcher Xiaoyu Li.
This approach has the possibility of using the power of a large number of complex chemical diversity in the DNA-coded chemical library to facilitate the discovery of membrane proteins, a technique that is an effective tool for charactertation of mating-target interactions and may in the future lead to new revelations in the development of high-volume screening methods to facilitate the capture of membrane proteins.
: 1 Huang, Y., Meng, L., Nie, Q. et al. Selection of DNA-encoded chemical libraries against endogenous membrane proteins on live cells. Nat. Chem. 13, 77–88 (2021). doi：10.1038/s41557-020-00605-x 【2】Chemists and collaborators develop a new drug discovery strategy for "undruggable" drug targets by The University of Hong Kong