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
Five density functionals, CAM-B3LYP, LC-ωPBE, MN12SX, N12SX and ωB97XD, in connection with the Def2TZVP basis set were assessed together with the SMD solvation model for the calculation of the molecular and chemical...Five density functionals, CAM-B3LYP, LC-ωPBE, MN12SX, N12SX and ωB97XD, in connection with the Def2TZVP basis set were assessed together with the SMD solvation model for the calculation of the molecular and chemical reactivity properties of the Cholecystokinin peptide hormone (CCK-8) in the presence of water. All the chemical reactivity descriptors for the systems were calculated via Conceptual Density Functional Theory (CDFT). The potential bioavailability and druggability as well as the bioactivity scoresfor CCK-8 were predicted through different methodologies already reported in the literature which have been previously validated during the study of different peptidic systems. The conclusion was that the CCK-8 peptide will be moderately bioactive regarding all the interactions.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
目的分析消化内科门诊胃食管反流样症状患者口服质子泵抑制剂(PPIs)的规范性与合理性,为临床提供参考。方法选取2017年7月1日~2022年12月31日消化内科门诊以胃食管反流样症状为主诉且完善内镜检查及食管24 h pH值监测的患者200例,统计患...目的分析消化内科门诊胃食管反流样症状患者口服质子泵抑制剂(PPIs)的规范性与合理性,为临床提供参考。方法选取2017年7月1日~2022年12月31日消化内科门诊以胃食管反流样症状为主诉且完善内镜检查及食管24 h pH值监测的患者200例,统计患者PPIs的使用情况,分析PPIs用药的合理性和规范性。结果200例患者中,使用PPIs患者有182例,其中102例(56.04%)患者长期服用PPIs时间超过3个月,服用的PPIs中以雷贝拉唑钠肠溶胶囊占比较重,其次为奥美拉唑肠溶胶囊、艾司奥美拉唑肠溶胶囊、泮托拉唑钠肠溶胶囊、兰索拉唑肠溶片;182例患者中有111例不合理用药者(占比60.99%),包括71例预防用药不合理者(占比39.01%)和40例治疗用药不合理者(占比21.98%);111例不合理用药的症状分布中以反流、烧心为主要症状的有63例,占比较重,为56.76%,其次为胸骨后不适、嗳气、腹痛、咳嗽等相关症状;182例使用过PPIs患者中,幽门螺杆菌感染者有74例(40.66%),仅12例(6.59%)在服用PPIs前进行了^(13)C呼气试验的检测,明确了有无幽门螺杆菌感染。结论某院普遍存在PPIs药物不合理应用现象,因此,应加强PPIs的科普与规范化使用。展开更多
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.
文摘Five density functionals, CAM-B3LYP, LC-ωPBE, MN12SX, N12SX and ωB97XD, in connection with the Def2TZVP basis set were assessed together with the SMD solvation model for the calculation of the molecular and chemical reactivity properties of the Cholecystokinin peptide hormone (CCK-8) in the presence of water. All the chemical reactivity descriptors for the systems were calculated via Conceptual Density Functional Theory (CDFT). The potential bioavailability and druggability as well as the bioactivity scoresfor CCK-8 were predicted through different methodologies already reported in the literature which have been previously validated during the study of different peptidic systems. The conclusion was that the CCK-8 peptide will be moderately bioactive regarding all the interactions.
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。
文摘目的分析消化内科门诊胃食管反流样症状患者口服质子泵抑制剂(PPIs)的规范性与合理性,为临床提供参考。方法选取2017年7月1日~2022年12月31日消化内科门诊以胃食管反流样症状为主诉且完善内镜检查及食管24 h pH值监测的患者200例,统计患者PPIs的使用情况,分析PPIs用药的合理性和规范性。结果200例患者中,使用PPIs患者有182例,其中102例(56.04%)患者长期服用PPIs时间超过3个月,服用的PPIs中以雷贝拉唑钠肠溶胶囊占比较重,其次为奥美拉唑肠溶胶囊、艾司奥美拉唑肠溶胶囊、泮托拉唑钠肠溶胶囊、兰索拉唑肠溶片;182例患者中有111例不合理用药者(占比60.99%),包括71例预防用药不合理者(占比39.01%)和40例治疗用药不合理者(占比21.98%);111例不合理用药的症状分布中以反流、烧心为主要症状的有63例,占比较重,为56.76%,其次为胸骨后不适、嗳气、腹痛、咳嗽等相关症状;182例使用过PPIs患者中,幽门螺杆菌感染者有74例(40.66%),仅12例(6.59%)在服用PPIs前进行了^(13)C呼气试验的检测,明确了有无幽门螺杆菌感染。结论某院普遍存在PPIs药物不合理应用现象,因此,应加强PPIs的科普与规范化使用。
