Drug-receptor interaction analysis has been broadly adopted as a tool for the evaluation of the drug-like property.Nowadays,growing evidence has demonstrated that drug e fficacy and safety are highly related to reside...Drug-receptor interaction analysis has been broadly adopted as a tool for the evaluation of the drug-like property.Nowadays,growing evidence has demonstrated that drug e fficacy and safety are highly related to residence time,which equals the reciprocal of the dissociation rate constant(k_(d))of a drug to its target protein.Using endothelin receptor A(ET_(A)R)as a probe,we immobilized the receptor on the surface of macroporous silica gel through a covalent interaction between the epidermal growth factor tyrosine kinase(EGFR)at the C terminal of ET_(A)R and the covalent inhibitor ibrutinib modified on the gel in a one-step fashion.The a ffinity stationary phase was used to semi-quantitatively determine the residence time of natural products on ET_(A)R and evaluate their drug-like property.The k_(d)values of three specific ligands(bosentan,macitentan,and ambrisentan)to ET_(A)R were determined by nonlinear chromatography,peak profiling and peak_(d)ecay.Compared the data determined in free solution of the three methods,peak profiling is considered as the best-fit method for k_(d)determination.Thus,peak profiling was applied for predicting the residence time of three natural products(ferulic acid,berberine,and palmatine)on ET_(A)R.With the longest residence time of 61.11±3.47 s on ET_(A)R,palmatine was evaluated as the most potent compound,which could be developed as a long-acting lead for the receptor.We demonstrate that the high-performance a ffinity chromatography with immobilized ET_(A)R is an alternative for the semi-quantitative measurement of residence time for the drug-like property evaluation of natural products.展开更多
In China,an estimated 48.42-82.11 million individuals are affected by rare diseases.This estimate is derived from the Orphanet database,based on the global population of 7.55 billion and China's population of 1.39...In China,an estimated 48.42-82.11 million individuals are affected by rare diseases.This estimate is derived from the Orphanet database,based on the global population of 7.55 billion and China's population of 1.39 billion in 2017(source:National Bureau of Statistics of China)[1,2].展开更多
基金the National Natural Science Foundation of China(22074118,21775119,21974107)the Key Research and Development Program of Shaanxi Province(2020ZDLSF0507,2018KWZ-05)Science and Technology Major Project of Tibet Autonomous Region(XZ202101ZD0019G)for the support of this work
文摘Drug-receptor interaction analysis has been broadly adopted as a tool for the evaluation of the drug-like property.Nowadays,growing evidence has demonstrated that drug e fficacy and safety are highly related to residence time,which equals the reciprocal of the dissociation rate constant(k_(d))of a drug to its target protein.Using endothelin receptor A(ET_(A)R)as a probe,we immobilized the receptor on the surface of macroporous silica gel through a covalent interaction between the epidermal growth factor tyrosine kinase(EGFR)at the C terminal of ET_(A)R and the covalent inhibitor ibrutinib modified on the gel in a one-step fashion.The a ffinity stationary phase was used to semi-quantitatively determine the residence time of natural products on ET_(A)R and evaluate their drug-like property.The k_(d)values of three specific ligands(bosentan,macitentan,and ambrisentan)to ET_(A)R were determined by nonlinear chromatography,peak profiling and peak_(d)ecay.Compared the data determined in free solution of the three methods,peak profiling is considered as the best-fit method for k_(d)determination.Thus,peak profiling was applied for predicting the residence time of three natural products(ferulic acid,berberine,and palmatine)on ET_(A)R.With the longest residence time of 61.11±3.47 s on ET_(A)R,palmatine was evaluated as the most potent compound,which could be developed as a long-acting lead for the receptor.We demonstrate that the high-performance a ffinity chromatography with immobilized ET_(A)R is an alternative for the semi-quantitative measurement of residence time for the drug-like property evaluation of natural products.
基金supported by the National Key Research and Development Program of China(2022YFC2703100)The Ministry of Finance of the People's Republic of China funded the UPWARDS projectthe National Health Commission of the People's Republic of China(NHC)for supporting this study。
文摘In China,an estimated 48.42-82.11 million individuals are affected by rare diseases.This estimate is derived from the Orphanet database,based on the global population of 7.55 billion and China's population of 1.39 billion in 2017(source:National Bureau of Statistics of China)[1,2].
