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
Lipinski’s “Rule of Five” was introduced for predicting oral bioavailability to describe drug-like molecules. For the purpose of this research the rules were used to separate potential inhibitors of HIV-1 integrase...Lipinski’s “Rule of Five” was introduced for predicting oral bioavailability to describe drug-like molecules. For the purpose of this research the rules were used to separate potential inhibitors of HIV-1 integrase (1BIS.pdb) into two groups: drug-like and nondrug-like. If one of Lipinski’s “Rule of Five” was not followed the potential inhibitor was classified as nondrug-like. Thirty molecules were identified from the literature, twenty-four drug-like and six nondrug-like, that were docked into the active site of 1BIS.pdb (considered the non-mutated protein) and two mutant models, Y143R and N155H. These are two of the mutations that have led to increased resistance to HIV-1 integrase drugs such as raltegravir and elvitegravir. The computational software, ICM-Pro (Molsoft L.L.C.), was used to determine the estimated binding energy (EBE) of the drug/protein complex. It was found that the nondrug-like molecules generally had a more negative EBE, that is, tighter binding with 1BIS. pdb, though there were several exceptions in the drug-like group. With the protein mutant model Y143R, the majority of drug-like (58%) and nondrug-like molecules (67%) had tighter binding. However, for the mutant model N155H, there was the same percent (46%) of drug-like molecules with tighter binding with the mutant model as with 1BIS.pdb. The drug-like molecules were used when there was a ≥1 kcal/mole difference between 1BIS.pdb and either of the two mutant models to suggest a pharmacophore with structural characteristics for an HIV-1 integrase inhibitor.展开更多
With the growing urgency of potential catastrophic climate changes due to anthropogenic CO2 emissions,numerous efforts have been devoted to development of synthetic protocols using CO2 as a building block in organic r...With the growing urgency of potential catastrophic climate changes due to anthropogenic CO2 emissions,numerous efforts have been devoted to development of synthetic protocols using CO2 as a building block in organic reactions, but the general applicability to complex drug-like substrates remains a challenge.We develop a general protocol for scalable direct N-methylation of a wide-scope drug-like amines using CO2 and polymethylhydrosiloxane-a nontoxic, aerobically-stable hydrosilane considered as an industrial waste-via simple inorganic base catalysis. A rare application of the Sabatier principle in organic chemistry led to the discovery of cheap, nontoxic K3PO4 as an efficient catalyst. Preparations of a wide-scope drug-like amines with carbon-isotope label were also successfully achieved, enabling direct use of CO2 in studies of drug absorption, distribution, metabolism and excretion.展开更多
使用比较分子力场分析法(CoMFA)和比较分子相似性指数法(CoMSIA)对33个已报道的喹啉酮类BRD4抑制剂进行3D-QSAR模型建立,研究了其化学结构和生物活性间的关系,并用计算机辅助药物设计(computer-aided drug design,CADD)设计出7个喹啉酮...使用比较分子力场分析法(CoMFA)和比较分子相似性指数法(CoMSIA)对33个已报道的喹啉酮类BRD4抑制剂进行3D-QSAR模型建立,研究了其化学结构和生物活性间的关系,并用计算机辅助药物设计(computer-aided drug design,CADD)设计出7个喹啉酮类抑制剂。结果表明,建立的CoMFA(q^(2)=0.926,r^(2)=0.997,r^(2)_(pred)=0.744)和CoMSIA(q^(2)=0.939,r^(2)=0.991,r^(2)_(pred)=0.786)模型具有较好的预测能力,基于这些模型设计的7个新喹啉酮类BRD4抑制剂具有高活性,并对其进行ADMET性质评价和类药性分析。以上研究结果有助于改造和开发更加有效的喹啉酮类BRD4抑制剂。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.
文摘Lipinski’s “Rule of Five” was introduced for predicting oral bioavailability to describe drug-like molecules. For the purpose of this research the rules were used to separate potential inhibitors of HIV-1 integrase (1BIS.pdb) into two groups: drug-like and nondrug-like. If one of Lipinski’s “Rule of Five” was not followed the potential inhibitor was classified as nondrug-like. Thirty molecules were identified from the literature, twenty-four drug-like and six nondrug-like, that were docked into the active site of 1BIS.pdb (considered the non-mutated protein) and two mutant models, Y143R and N155H. These are two of the mutations that have led to increased resistance to HIV-1 integrase drugs such as raltegravir and elvitegravir. The computational software, ICM-Pro (Molsoft L.L.C.), was used to determine the estimated binding energy (EBE) of the drug/protein complex. It was found that the nondrug-like molecules generally had a more negative EBE, that is, tighter binding with 1BIS. pdb, though there were several exceptions in the drug-like group. With the protein mutant model Y143R, the majority of drug-like (58%) and nondrug-like molecules (67%) had tighter binding. However, for the mutant model N155H, there was the same percent (46%) of drug-like molecules with tighter binding with the mutant model as with 1BIS.pdb. The drug-like molecules were used when there was a ≥1 kcal/mole difference between 1BIS.pdb and either of the two mutant models to suggest a pharmacophore with structural characteristics for an HIV-1 integrase inhibitor.
基金supported by the National Natural Science Foundation of China(U1532135)
文摘With the growing urgency of potential catastrophic climate changes due to anthropogenic CO2 emissions,numerous efforts have been devoted to development of synthetic protocols using CO2 as a building block in organic reactions, but the general applicability to complex drug-like substrates remains a challenge.We develop a general protocol for scalable direct N-methylation of a wide-scope drug-like amines using CO2 and polymethylhydrosiloxane-a nontoxic, aerobically-stable hydrosilane considered as an industrial waste-via simple inorganic base catalysis. A rare application of the Sabatier principle in organic chemistry led to the discovery of cheap, nontoxic K3PO4 as an efficient catalyst. Preparations of a wide-scope drug-like amines with carbon-isotope label were also successfully achieved, enabling direct use of CO2 in studies of drug absorption, distribution, metabolism and excretion.
文摘使用比较分子力场分析法(CoMFA)和比较分子相似性指数法(CoMSIA)对33个已报道的喹啉酮类BRD4抑制剂进行3D-QSAR模型建立,研究了其化学结构和生物活性间的关系,并用计算机辅助药物设计(computer-aided drug design,CADD)设计出7个喹啉酮类抑制剂。结果表明,建立的CoMFA(q^(2)=0.926,r^(2)=0.997,r^(2)_(pred)=0.744)和CoMSIA(q^(2)=0.939,r^(2)=0.991,r^(2)_(pred)=0.786)模型具有较好的预测能力,基于这些模型设计的7个新喹啉酮类BRD4抑制剂具有高活性,并对其进行ADMET性质评价和类药性分析。以上研究结果有助于改造和开发更加有效的喹啉酮类BRD4抑制剂。
