Universal construction method for protein-targeting chimeric molecule compound

Abstract

The invention discloses a universal construction method for a protein-targeting chimeric molecule compound. The objective of the invention is to provide a method for adjusting the level of proteins by degrading the proteins through targeted ubiquitination. The construction method mainly comprises the following steps: 1) locating and analyzing a three-dimensional structure of a target protein and predicting active sites; 2) selecting a compound database; 3) virtually screening ligand compounds having high degrees of adaption to the target protein by using a computer; 4) acquiring the screened ligand compounds and screening an optimal ligand compound of the target protein through detection of interaction between micromolecules and the proteins; 5) constructing a protein-targeting chimeric molecule compound composed of the optimal ligand compound of the target protein, ubiquitin ligase E3 identification ligand and Linker connecting the optimal ligand compound of the target protein to the ubiquitin ligase E3 identification ligand by using a combination manner simulated by the computer; and 6) chemically synthesizing the protein-targeting chimeric molecule compound. With the method provided by the invention, the protein-targeting chimeric molecule compound can be rapidly and highly efficiently prepared, and specific degradation of intracellular target proteins is realized.

Description

technical field [0001] The invention relates to the technical field of targeting ubiquitination to degrade proteins, in particular to a method for constructing chimeric molecular compounds targeting proteins. Background technique [0002] Ubiquitin is a class of low-molecular-weight proteins, and ubiquitination refers to the process in which ubiquitin molecules specifically modify target proteins under the action of a series of enzymes. Organisms tag proteins that need to be degraded with ubiquitination, and the tagged proteins are then degraded in the proteasome. The ubiquitination process controls the degradation of most proteins in human cells, and participates in the regulation of almost all life activities such as cell cycle, proliferation, apoptosis, differentiation, metastasis, gene expression, transcription regulation, signal transmission, damage repair, inflammation and immunity . In recent years, studies on the ubiquitin-proteasome degradation system (UPP) in tum...

AI Technical Summary

Problems solved by technology

[0008] In the process of Protac research, due to the relatively conservative functional domain of E3, breakthroughs have been made in the research of small molecule peptides that can combine with the functional domain of E3. The small-molecule ligand compound that binds to the target protein is an extremely tedious, time-consuming and labor-intensive task, and requires researchers to have a considerable background in chemical synthesis to be competent, which has become a technical bottleneck in the construction of chimeric molecular compounds targeting proteins

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