On August 5, a Chinese scholar’s paper was published in the Journal of science and progress, in which a microscopic picture of “drug targeting” was published. The photo shows: when the drug molecule (Thioflavin T) wants to combine with the target protein in the body of life, it is not a single molecule to bind the protein as people imagine, but it is automatically assembled like a “Lego building block” and “hit the target” together. This “dexterity” is completely different from the previous people’s imagination. What disruptive changes may this new discovery bring about? Why haven’t you taken such pictures before? What does drug molecules rely on to assemble automatically like LEGO? With these questions in mind, on August 12, the reporter of science and technology daily interviewed Wang chenxuan, an associate researcher in the Institute of basic medicine, Chinese Academy of Medical Sciences, who is one of the corresponding authors of the paper. < p > < p > “there is a classic” lock and key model “in the textbook, which means that the drug molecule must be closely connected with the protein to” hit the target “, just like a key to open a lock. However, the present microscopic observation results show that the drug molecule” works “in an oligomeric state, or we only need half a key to unlock the lock.” Wang chenxuan told Science and Technology Daily that this is the first time that scientists can directly see the state of “drug targeting”, which can be used to guide the design of drug molecules. < / P > < p > let’s talk about the protagonist of this picture. They are the drug molecule Thioflavin T, and its target molecule, amylin (a type of amyloid protein). < / P > < p > why choose these two protagonists for research? Wang chenxuan said that as a life macromolecule, once the protein is wrong, it will often “entangle” and be disordered, changing from the correct folding conformation to the wrong folding conformation, and finally forming amyloid precipitation. Therefore, amyloid protein is related to many diseases. The most familiar amyloid protein is β – amyloid protein, which is found to occur frequently in the nerve cells of Alzheimer’s disease patients. Many pharmaceutical companies have invested a lot of money to study how to make these amyloid precipitates disappear, but so far they have not succeeded. There are also type 2 diabetes mellitus, Huntington’s disease and so on. Amyloid protein is found in these diseases. Therefore, it is helpful for many diseases to study the mechanism of their interaction with drug molecules. Thioflavin t was paired in pairs, in a group of four or even in groups of six. In academic terms, the research team found that the binding structure of Thioflavin t on the surface of receptor protein exists in four oligomers, namely dimer (head to tail), dimer (side by side), tetramer and hexamer. Before that, people either thought that drug molecules could only be “single” or conjectured their combination by “blind calculation”, but without any evidence, it would be even more impossible to guide practice. After that, drug designers can boldly apply the selective oligomerization effect to the structural design and optimization of drug molecules. By understanding the mechanism of drug oligomerization and manipulating the oligomerization structure, drug clusters rather than single drug molecules are used as “units” to target receptor proteins. It is difficult to take pictures of proteins, first by crystal diffraction and then by freeze electron microscopy, but not all proteins can be photographed successfully. The reason is that the proteins must be arranged in an orderly array to meet the imaging requirements. < / P > < p > “it’s like, only the PLA square array in the military parade can be imaged, while the mass party square array behind can’t be photographed.” Wang chenxuan made a special image of the example, so to film the protein molecules binding to drug molecules, we need to use new camera equipment. < p > < p > the scanning tunneling microscope (STM) shoulders the heavy responsibility. “It was originally used by physicists to detect the microstructure of atoms and subatoms, with ultra-high resolution.” Wang chenxuan said that the introduction of physical equipment into the biological field was a matter in the 1990s, and new research and development of hardware, software and algorithms of the equipment was needed. The Chinese team entered this field earlier in the world. It uses the tunneling effect in quantum mechanics to capture the “pattern” of protein and drug molecules directly by recording the electrons passing through the sample. The initial STM operation must be in vacuum. < / P > < p > the Chinese team of scientists solved the problem of using scanning tunneling microscope (STM) to observe chemical molecules at atmospheric temperature for the first time in the world. < / P > < p > “after several generations of continuous inheritance, continuous transformation of equipment and development of new data acquisition methods, we can fully demonstrate its ability.” Wang chenxuan said. < p > < p > in order to take the first microscopic picture of “drug targeting”, Wang chenxuan, Yu Lanlan, and Zhang Wenbo from the basic Institute of Medical College, together with Wang Chen, Yang Yanlian, Fang Qiaojun team from the National Center for nanoscience for many years, have not only invented a series of patented technologies, such as protein adsorption technology, molecular chaperone fixation technology, scanning probe pulse technology and so on The whole process of “taking photos” is optimized and explored. < / P > < p > “the whole set of (photographing) technology is very complex, and it is difficult to form a copying process. It can only be like word of mouth transmission between craftsmen, which requires knowledge, experience and speculation. Professionals may need a year or several years of training time to follow along to master it systematically.” Wang chenxuan said. As the saying goes, “one minute on the stage, ten years off the stage.”. The first “drug targeting” microscope not only condenses the accumulation of several generations in this field, but also presents the innovation of a team of multi-disciplinary talents such as biology, physics, imaging and so on. < / P > < p > A: it can simplify the drug synthesis path. “Drug design is a key process. People have known the structure of a disease-related protein. To design a reverse drug, we need organic chemists and theoretical chemists of computer-aided drug design to build a key large enough to match the active center of the protein Wang chenxuan explained to the science and Technology Daily that the longer the drug is synthesized, the more difficult it is. Each group is like “sticking to the arm”. When it comes to industrialization, the requirements for the process are increasing exponentially. If the drug actually only needs to synthesize a very small part of the original, 1 / 4 or 1 / 8, then the difficulty will be greatly reduced. < / P > < p > “when small molecules enter the body, they can pass through barriers that cannot be crossed by large molecules.” Wang chenxuan introduced, such as an anti-tumor drug, to enter the solid tumor is very difficult. Because of the high degree of liquefaction inside the solid tumor, the pressure is very high, the macromolecules can not reach at all, but the small molecules are different. They can diffuse freely and reach the action site directly. After assembling, they will play a better role. < / P > < p > “we clearly observed four kinds of oligomers of drug molecules in the microscope, which suggests that we should consider drug clusters as the basic unit to play a role in drug design.” Therefore, the interaction between molecules should be taken into account in drug design. According to Wang chenxuan, there are still many theories to be improved. For example, further research can be carried out on the old drugs, according to the previous drug data, to prove the method of interaction with protein, which kind of ordered structure exists. < / P > < p > “at the same time, we need to know the energy required for drug molecule binding, so we can control whether the molecule exists in dimer or other oligomeric form through energy.” Wang chenxuan said that many theories in the field of physical chemistry were also involved to support it. < / P > < p > there is still a long way to go to greatly simplify the current drug design process. Wang chenxuan said the microscope photo proves the feasibility of this path. The team’s research provides a tool and a set of theoretical basis, but how to achieve it, how to integrate theory with practice on this basis, and really apply it to clinical drug research and development still needs a lot of work. < p > < p > Architecture has the concept of less is more. The first microscopic picture of “drug targeting” tells us that this idea may also apply to drug design.