Screening method of TTR (transthyretin) small-molecule inhibitors

Abstract

The invention aims to establish an efficient, fast and reliable screening method of TTR (transthyretin) small-molecule inhibitors, overcomes the defects of the prior art and is applicable to design of medicines for amyloidosis caused by TTR fibrosis. A small-molecule database is screened and predicted by means of 3D-QSAR (3-dimensional quantitative structure activity relationship), molecular docking, pharmacophore models and the like; small molecules capable of serving as lead compounds are determined preliminarily; further cell screening is performed. The screening method is fast and efficient; a plurality of drug screening and design methods based on receptors and ligands are applied; accordingly, reliability of screening results is improved greatly. Cell levels are subjected to biological screening by lead compounds obtained by screening, so that screening speed is higher and development and search cycle of novel inhibitors is shortened.

Description

technical field [0001] The invention relates to a method for drug screening and prediction, in particular to a method for drug screening and prediction of a small molecule inhibitor with TTR protein as a receptor. Background technique [0002] Thyroid binding prealbumin (Transthyretin, referred to as TTR), also known as transthyretin, is a plasma transport protein, the main function in the human body is to transport thyroid hormone (thyroxine) and vitamin A. TTR is produced by the liver, eyes, and choroid plexus, and is mainly found in cerebrospinal fluid and plasma. Among them, the content in human plasma is about 0.2 mg / mL. [0003] TTR was first isolated and sequenced from plasma by D. Goodman. It is a tetrameric protein with a molecular weight of 62Kda and each monomer consists of 127 amino acid residues. The TTR monomer is composed of two β-sheets (β-sheet) inside and outside, each β-sheet contains four β-sheet strands (β-strands), and there is a stretch of 9 amino ac...

AI Technical Summary

Problems solved by technology

However, under the action of some unnatural factors, TTR may undergo pathological changes, resulting in metabolic disorders and the production of amyloid fibers, resulting in familial amyloid polyneuropathy, familial amyloid cardiomyopathy, senile systemic amyloidosis, etc.

It is generally believed that the aggregation of TTR is very important for the cause of amyloidosis, but the reason for its aggregation is not clear

Scientists believe that the TTR tetramer is sometimes unstable, causing it to disassemble, and that if errors occur when it refolds after disassembly, it may form fibrous substances

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