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The Role of Dynamic Combinatorial Chemistry in the Discovery of Lead Compounds

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In the new drug development process, wise selection of lead candidates can reduce the high proportion of drug elimination and the high cost of drug candidates that continue to increase in the development process. Discovery of lead compounds and optimization of lead compounds are critical to medical research and development. The combination of lead compound technology and high-throughput screening can predict drug failure and make investment highly effective.


A large number of lead compounds are obtained through compound activity testing and screening. With the continuous development of screening technology, especially the continuous maturity of high-throughput screening technology, the discovery efficiency of lead compounds has been greatly improved. In order to solve the challenge to the diversity and quantity of compounds brought by high-throughput screening technology, combinatorial chemistry technology came into being. Combinatorial chemistry is a technology that can generate a huge molecular library of molecular diversity, and has played an important role in the discovery of drug lead compounds and lead compound optimization. Combinatorial chemistry methods can quickly generate a large number of compound libraries with rich molecular diversity, which to a certain extent breaks through the problem of insufficient compound quantity and diversity in drug screening.

Dynamic combinatorial chemistry is a new research method developed on the basis of combinatorial chemistry using the characteristics of supramolecular chemistry. Dynamic combinatorial chemistry can connect the building units in the dynamic combinatorial chemistry library as reversible covalent bonds. Each building unit uses reversible covalent reactions to convert between each other. Under the induced drive of the target molecule, it can form a strong interaction with the target molecule. The active compounds are continuously enriched, the chemical equilibrium shifts to the direction of generating the dominant compound, and the amount of other non-dominant compounds is continuously reduced, finally achieving the purpose of screening dominant compounds that have a strong interaction with the target.

The research phase of candidate drugs includes four important links: target determination, model establishment, lead compound discovery, and lead compound optimization. Medicilon provides customers with new drug development services covering various targets and disease fields, including active compound discovery and target verification. , Lead compounds are optimized to the selection of preclinical drug candidates.

At present, dynamic combinatorial chemistry has played a role in the discovery of exogenous lectins, enzyme inhibitors, chiral adenosine ligands and the synthesis of molecular capsule compounds. Its applications in the discovery of lead compounds mainly include the following:

(1) Discovery of lectin inhibitors

The application of dynamic combinatorial chemistry methods can successfully generate and screen ligands and receptor compounds. Biological targets play an important role in finding lead compounds. Like other biotechnologies, sugar-bonded proteins have great application potential in the field of drug discovery and can be used as targets for constructing dynamic combinatorial chemical libraries. Some researchers have used the plant lectin concanavalin A as the target, the sugar with sulfhydryl group as the building unit, used the exchange reaction to construct a dynamic combinatorial chemical library, and screened the concomitant knife through the interaction between the sugar compound and the lectin As a legumein A inhibitor, the lead compound 1-thiol-6-S-mannose was discovered.

(2) Discovery of enzyme inhibitors

The heteronuclear dimer formed by the lead compound can improve the activity and selectivity of antitumor drugs. The researchers used two tubulin receptors, thiocolchicine and podophyllotoxin as building blocks, and dimercapto-diacetyl groups as the connecting bridge. Using the disulfide exchange reaction, albumin and subtilisin (albumin) and subtilisin ( Subtilism) as the target, successfully constructed dimer conjugate base compounds with different length carbon chains. In vitro biological activity tests show that the activity of the dimer compound is not a simple addition of the activities of the two monomer compounds, which reflects the inducing function of the biological target. Although no dimer compounds with better activity than the raw materials were screened in this dynamic library, it was proved that using two types of lead compounds as raw materials can construct a large-scale dynamic combinatorial chemical library of dimers, and biological targets can induce the generation of dominant compounds. It provides a new way for the research of anti-tumor drugs.

(3) Discovery of chiral adenosine ligands

Chiral recognition plays an important role in the process of life, and the discovery of chiral recognition active substances for specific targets is an important topic in the field of drug research. (-)-Adenosine represents an important class of receptors. Some researchers have used (-) adenosine as the target and the racemic cyclic hydrazone dipeptide as the substrate, and constructed a dynamic combinatorial chemical library of cyclic oligomers through the reversible exchange reaction of hydrazone. Driven by the selective induction of (-)-adenosine, the number of chiral compounds capable of forming strong interactions with (-)-adenosine is increasing, becoming the dominant compound in the system, and this compound is the potential (-)- Adenosine receptor inhibitors. The results of this study show that with racemate as the starting material, chiral ligands of the target can be found through the induction of chiral targets. This method has a good application in the selective discovery of chiral ligands for important biological targets prospect.

(4) Synthesis of molecular capsule compound

Molecular capsule compounds have aroused the research enthusiasm of many scientists due to their unique structures and properties. The design and construction of container-like molecules has become a new research focus. The dynamic combinatorial chemistry method overcomes the instability of supramolecular self-assembly molecules and the difficult control of irreversible covalent reactions, and is an attractive method for synthesizing molecular capsules and other compounds.

Based on the special properties of dynamic combinatorial chemistry, applying it to the drug discovery process is a good way to find lead compounds. Dynamic combinatorial chemistry can design, synthesize and screen specific ligands for biological macromolecules in a targeted manner. It uses reversible chemical reactions to dynamically combine and exchange structural units in the combinatorial library. After adding the target molecule, the active ingredients in the library are selectively identified and screened. Therefore, it has broad application prospects in the field of new drug development.

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