A method for preparing DNA-encoded compound library, starting head fragment compound and prepared DNA-encoded compound

Abstract

The invention discloses a method for preparing a DNA-encoded compound library containing two or more pharmacophore. The novel starting head fragment used in the method has two or more chemically modifiable linking groups. The starting head The fragment consists of a nucleotide chain, the 5' and 3' of the nucleotide chain respectively have a group R that can undergo chemical reactions 1 and R 2 , there are n linkers on the nucleotide chain, the linker is a long chain extended from the modified nucleotide monomer on the nucleotide chain, and each long chain has a chemically reactive Site G. The site G of the initial head fragment reacts with the fragment compound respectively to generate the fragment compound residue B that connects the site G and the fragment compound to form a DNA-encoded compound, and finally can obtain a compound containing two or more pharmacophore DNA-encoded compound library. A DNA coded compound library containing two or more pharmacophores can be obtained efficiently, simply and rapidly through the method and the starting head fragment of the invention.

Description

technical field [0001] The present invention relates to the field of combinatorial chemistry, in particular to a method for preparing a library of DNA-encoded compounds containing two or more pharmacophore, the prepared DNA-encoded compound and the initial head segment compound. This method adopts a novel starting head fragment for the construction of a DNA-encoded compound library. The starting head fragment has two or more linking groups that can be chemically modified. A DNA-encoded compound library of one or more pharmacophores. Background technique [0002] A drug target refers to a biological molecule that has a causal relationship with the occurrence of a certain disease or participates in the development of the disease, and achieves the purpose of treating the disease by regulating its activity through a certain type of drug. Since the introduction of in vitro screening (invitro) Since its conception, with the advancement of molecular biology, proteomics, genomics a...

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Problems solved by technology

However, with the further research, people found that single-target drugs also have obvious shortcomings: first, most diseases are not caused by a single gene or target, and diseases caused by abnormal single genes or targets account for only a small number; Drug targets are not unique to a certain disease. Most of them have multiple biological functions. Excessively inhibiting or activating a certain biomolecule in the body may affect the function of related biomolecules while interfering with its own biological functions, resulting in Side effects; third, it is difficult to find molecules that only act on a single target

However, this method also has great limitations. First, there are few cycles, and the number of compound molecules obtained is limited. Generally, it is difficult to reach the million level. Compared with the DNA Recording Molecule Library (DRCL), there are hundreds of millions, or even billions. The libraries of compound molecules are not at the same level at all; the second is that two or three sub-libraries need to be synthesized respectively, which requires a large workload and a long synthesis cycle; third, the nucleotide single strands between these sub-libraries must have a long The fixed base sequence is used for base pairing to form double strands, and the number of bases that can be used for coding accounts for a relatively small proportion; fourth, the nucleotide coding regions of different sub-libraries need to be integrated into one sub-library through Klenow fill-in On a single nucleotide strand, the coding conversion is cumbersome; fifth, it is mainly used for dual-target drug screening. Due to the limitation of the nucleotide single strand itself, it is difficult to be used for the screening of more targets

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