Although the GABAA receptor(GABAAR)has been proposed as the main action site for sevoflurane,isoflurane,halothane,enflurane,propofol,and benzodiazepines(BZDs),binding of these anesthetics with high-resolution structur...Although the GABAA receptor(GABAAR)has been proposed as the main action site for sevoflurane,isoflurane,halothane,enflurane,propofol,and benzodiazepines(BZDs),binding of these anesthetics with high-resolution structures of the GABAAR have been rarely examined by comparative docking analyses.Moreover,various combinations of ligands on more GABAARs with various subtypes need to be analyzed to understand the elaborate action mechanism of GABAARs better because some GABAA ligands showed specificity toward the distinct subtypes of the GABAAR.Methods:We performed in silico docking analysis to compare the binding modes of sevoflurane,isoflurane,halothane,enflurane,propofol,and BZDs to the GABAAR based on one of the most recently provided 3D structures.We performed the docking analysis and the affinity-based ranking of the binding sites.Results:Our docking studies revealed that isoflurane,halothane,and enflurane docked in an extracellular domain(ECD)on GABAARs,in contrast to sevoflurane.Conclusion:Our results supported a multi-site mechanism for the allosteric modulation of propofol.Propofol was bound to the pore or favored various subsites in the transmembrane domain(TMD).Our result confirmed that different chemically related BZD ligands interact via distinct binding modes rather than by using a common binding mode,as previously suggested.展开更多
With a view to finding out precisely how small peptides recognize a particular binding site of DNA, we have accomplished DNA binding studies of two peptides, H-Tyr-Arg-OH (YR) and H-Gly-Gly-His-OH (GGH) by using measu...With a view to finding out precisely how small peptides recognize a particular binding site of DNA, we have accomplished DNA binding studies of two peptides, H-Tyr-Arg-OH (YR) and H-Gly-Gly-His-OH (GGH) by using measurements in comparison with the binding between DNA and Hoechst 33258. The inhibition mode by YR and GGH to DNA binding of Hoechst 33258 was analyzed by Lineweaver-Burk plot which shows the plot of typical competitive inhibition at concentration of Hoechst 33258 from 3.66 ( 10-9 mol / L to 1.09 ( 10-8 mol / L. And it is concluded that YR binds to DNA in its minor groove (AT rich regions) with a binding constant K = 1.02 ( 108 (mol / L)-1. The GGH(s specificity is reduced at high concentration because it can also bind GC base pair.展开更多
Neuraminidase （NA）, a major surface glycoprotein of influenza virus with well-defined active sites, is an ideal plat- form for the development of antiviral drugs. However, a growing number of NA mutations have drug ...Neuraminidase （NA）, a major surface glycoprotein of influenza virus with well-defined active sites, is an ideal plat- form for the development of antiviral drugs. However, a growing number of NA mutations have drug resistance to today＇s inhibitors. Numerous efforts are made to explore the resistance mechanisms through understanding the structural changes in mutated NA proteins and the associated different binding profiles of inhibitors, via x-ray, nuclear magnetic resonance, electron microscopy, and molecular dynamics methods. This review presents the architectural features of mutated NA proteins, as well as the respective inhibitor sensitivities arising from these spatial differences. Finally, we summarize the resistance mechanisms of today＇s neuraminidase inhibitors and the outlook tbr the development of novel inhibitors.展开更多
组织蛋白酶K(Cathepsin K,CTSK)属于半胱氨酸蛋白酶,是抗骨质疏松药物研发的重要靶点,在破骨细胞中特异性高表达,对降解骨胶原基质至关重要。与临床常用的抑制骨吸收药物相比,CTSK抑制剂具有在不影响骨形成的情况下有效减少骨吸收的优...组织蛋白酶K(Cathepsin K,CTSK)属于半胱氨酸蛋白酶,是抗骨质疏松药物研发的重要靶点,在破骨细胞中特异性高表达,对降解骨胶原基质至关重要。与临床常用的抑制骨吸收药物相比,CTSK抑制剂具有在不影响骨形成的情况下有效减少骨吸收的优点。迄今为止,CTSK抑制剂的研发均因安全性不足而失败,原因是对皮肤和血管系统等非骨组织造成副作用。传统中药富含抑制骨吸收的活性物质,一些文献表明中药来源的CTSK抑制剂抗骨质疏松作用明显,且没有明显的不良反应。笔者拟综述近10年中药来源的CTSK抑制剂的研究进展,资料主要来源于中国知网、万方和Web of Science数据库,为开发中药CTSK抑制剂和治疗CTSK相关疾病提供参考。展开更多
原发免疫豁免部位大B细胞淋巴瘤(primary immune-privileged site large B-cell lymphoma,IP-DLBCLs)是世界卫生组织(WHO)淋巴样肿瘤分类第5版新的类别总称,指一组原发于免疫功能正常患者的免疫屏障之后部位的侵袭性B细胞淋巴瘤,起源于...原发免疫豁免部位大B细胞淋巴瘤(primary immune-privileged site large B-cell lymphoma,IP-DLBCLs)是世界卫生组织(WHO)淋巴样肿瘤分类第5版新的类别总称,指一组原发于免疫功能正常患者的免疫屏障之后部位的侵袭性B细胞淋巴瘤,起源于各自的解剖结构(如血脑、血网膜和血睾丸屏障)和各自原发部位的免疫调节系统所形成的免疫庇护所,并具有相同的免疫表型和分子特征,目前包括原发性中枢神经系统大B细胞淋巴瘤(primary central nervous system lymphoma,PCNSL)、原发睾丸大B细胞淋巴瘤(primary testicular large B-cell lymphoma,PTL)和原发玻璃体视网膜大B细胞淋巴瘤(primary vitreoretinal large B-cell lymphoma,PVRL)。该类疾病预后相对较差,目前尚无标准的治疗方案。Toll样受体(TLR)信号(通过MYD88突变)和B细胞受体(BCR)信号(通过CD79B突变)通路介导的NF-κB激活是三者发病的核心机制。该共同属性为这一类疾病的治疗提供了通用的靶点。BTK(Bruton’s tyrosine kinase,BTK)是上述信号通路的中心分子。因此,BTK抑制剂可能是这类疾病合理的治疗药物选择。本文将就BTK抑制剂治疗原发免疫豁免部位大B细胞淋巴瘤的作用机制、临床研究、不良反应及耐药问题进行综述。展开更多
SARS is a positive-stranded virus featuring the largest viral RNA genomes today. The viral main proteinase(Hydrolase), controlling the activities of SARS virus replication , is an attractive target for therapy. We det...SARS is a positive-stranded virus featuring the largest viral RNA genomes today. The viral main proteinase(Hydrolase), controlling the activities of SARS virus replication , is an attractive target for therapy. We determined crystal structure for transmissible gastroenteritis virus(TGEV) hydrolase, and constructed a homology model for SARS coronavirus proteinase on Silicon Graphics station by Insight Ⅱ molecule simulation software. The structure may reveal remarkable degree of conservation of the substrate binding sites. We design an imaginable peptide precursor for inhibitor, and the base shape of pocket and property of the residues may be used as a basis for designing anti-SARS drugs.展开更多
目的综述微管蛋白秋水仙碱结合位点抑制剂Combretastatin A-4(CA-4)类似物的研究进展。方法依据近期国内外公开发表的49篇文献,将CA-4类似物的研究进展分类、归纳并总结。结果微管蛋白秋水仙碱结合位点抑制剂(colchicine binding site i...目的综述微管蛋白秋水仙碱结合位点抑制剂Combretastatin A-4(CA-4)类似物的研究进展。方法依据近期国内外公开发表的49篇文献,将CA-4类似物的研究进展分类、归纳并总结。结果微管蛋白秋水仙碱结合位点抑制剂(colchicine binding site inhibitors,CBSI)具有增殖抑制和血管破坏双重活性,近年来备受抗肿瘤药物研究人员的关注。CA-4类似物的抗肿瘤活性突出且结构简单,是CBSI中的重要组成部分。本文对CA-4类似物的结构特点及其构效关系进行了归纳总结。结论利用CA-4类似物的构效关系归纳总结进行开发新药已成为研究热点。展开更多
文摘Although the GABAA receptor(GABAAR)has been proposed as the main action site for sevoflurane,isoflurane,halothane,enflurane,propofol,and benzodiazepines(BZDs),binding of these anesthetics with high-resolution structures of the GABAAR have been rarely examined by comparative docking analyses.Moreover,various combinations of ligands on more GABAARs with various subtypes need to be analyzed to understand the elaborate action mechanism of GABAARs better because some GABAA ligands showed specificity toward the distinct subtypes of the GABAAR.Methods:We performed in silico docking analysis to compare the binding modes of sevoflurane,isoflurane,halothane,enflurane,propofol,and BZDs to the GABAAR based on one of the most recently provided 3D structures.We performed the docking analysis and the affinity-based ranking of the binding sites.Results:Our docking studies revealed that isoflurane,halothane,and enflurane docked in an extracellular domain(ECD)on GABAARs,in contrast to sevoflurane.Conclusion:Our results supported a multi-site mechanism for the allosteric modulation of propofol.Propofol was bound to the pore or favored various subsites in the transmembrane domain(TMD).Our result confirmed that different chemically related BZD ligands interact via distinct binding modes rather than by using a common binding mode,as previously suggested.
文摘With a view to finding out precisely how small peptides recognize a particular binding site of DNA, we have accomplished DNA binding studies of two peptides, H-Tyr-Arg-OH (YR) and H-Gly-Gly-His-OH (GGH) by using measurements in comparison with the binding between DNA and Hoechst 33258. The inhibition mode by YR and GGH to DNA binding of Hoechst 33258 was analyzed by Lineweaver-Burk plot which shows the plot of typical competitive inhibition at concentration of Hoechst 33258 from 3.66 ( 10-9 mol / L to 1.09 ( 10-8 mol / L. And it is concluded that YR binds to DNA in its minor groove (AT rich regions) with a binding constant K = 1.02 ( 108 (mol / L)-1. The GGH(s specificity is reduced at high concentration because it can also bind GC base pair.
基金Project supported by the National Natural Science Foundation of China(Grant Nos.11374237 and 11504287)Fundamental Research Funds for the Central Universities,China,China Postdoctoral Science Foundation(Grant No.2017M613147)Shaanxi Province Postdoctoral Science Foundation,China
文摘Neuraminidase （NA）, a major surface glycoprotein of influenza virus with well-defined active sites, is an ideal plat- form for the development of antiviral drugs. However, a growing number of NA mutations have drug resistance to today＇s inhibitors. Numerous efforts are made to explore the resistance mechanisms through understanding the structural changes in mutated NA proteins and the associated different binding profiles of inhibitors, via x-ray, nuclear magnetic resonance, electron microscopy, and molecular dynamics methods. This review presents the architectural features of mutated NA proteins, as well as the respective inhibitor sensitivities arising from these spatial differences. Finally, we summarize the resistance mechanisms of today＇s neuraminidase inhibitors and the outlook tbr the development of novel inhibitors.
文摘组织蛋白酶K(Cathepsin K,CTSK)属于半胱氨酸蛋白酶,是抗骨质疏松药物研发的重要靶点,在破骨细胞中特异性高表达,对降解骨胶原基质至关重要。与临床常用的抑制骨吸收药物相比,CTSK抑制剂具有在不影响骨形成的情况下有效减少骨吸收的优点。迄今为止,CTSK抑制剂的研发均因安全性不足而失败,原因是对皮肤和血管系统等非骨组织造成副作用。传统中药富含抑制骨吸收的活性物质,一些文献表明中药来源的CTSK抑制剂抗骨质疏松作用明显,且没有明显的不良反应。笔者拟综述近10年中药来源的CTSK抑制剂的研究进展,资料主要来源于中国知网、万方和Web of Science数据库,为开发中药CTSK抑制剂和治疗CTSK相关疾病提供参考。
文摘原发免疫豁免部位大B细胞淋巴瘤(primary immune-privileged site large B-cell lymphoma,IP-DLBCLs)是世界卫生组织(WHO)淋巴样肿瘤分类第5版新的类别总称,指一组原发于免疫功能正常患者的免疫屏障之后部位的侵袭性B细胞淋巴瘤,起源于各自的解剖结构(如血脑、血网膜和血睾丸屏障)和各自原发部位的免疫调节系统所形成的免疫庇护所,并具有相同的免疫表型和分子特征,目前包括原发性中枢神经系统大B细胞淋巴瘤(primary central nervous system lymphoma,PCNSL)、原发睾丸大B细胞淋巴瘤(primary testicular large B-cell lymphoma,PTL)和原发玻璃体视网膜大B细胞淋巴瘤(primary vitreoretinal large B-cell lymphoma,PVRL)。该类疾病预后相对较差,目前尚无标准的治疗方案。Toll样受体(TLR)信号(通过MYD88突变)和B细胞受体(BCR)信号(通过CD79B突变)通路介导的NF-κB激活是三者发病的核心机制。该共同属性为这一类疾病的治疗提供了通用的靶点。BTK(Bruton’s tyrosine kinase,BTK)是上述信号通路的中心分子。因此,BTK抑制剂可能是这类疾病合理的治疗药物选择。本文将就BTK抑制剂治疗原发免疫豁免部位大B细胞淋巴瘤的作用机制、临床研究、不良反应及耐药问题进行综述。
文摘SARS is a positive-stranded virus featuring the largest viral RNA genomes today. The viral main proteinase(Hydrolase), controlling the activities of SARS virus replication , is an attractive target for therapy. We determined crystal structure for transmissible gastroenteritis virus(TGEV) hydrolase, and constructed a homology model for SARS coronavirus proteinase on Silicon Graphics station by Insight Ⅱ molecule simulation software. The structure may reveal remarkable degree of conservation of the substrate binding sites. We design an imaginable peptide precursor for inhibitor, and the base shape of pocket and property of the residues may be used as a basis for designing anti-SARS drugs.
文摘目的综述微管蛋白秋水仙碱结合位点抑制剂Combretastatin A-4(CA-4)类似物的研究进展。方法依据近期国内外公开发表的49篇文献,将CA-4类似物的研究进展分类、归纳并总结。结果微管蛋白秋水仙碱结合位点抑制剂(colchicine binding site inhibitors,CBSI)具有增殖抑制和血管破坏双重活性,近年来备受抗肿瘤药物研究人员的关注。CA-4类似物的抗肿瘤活性突出且结构简单,是CBSI中的重要组成部分。本文对CA-4类似物的结构特点及其构效关系进行了归纳总结。结论利用CA-4类似物的构效关系归纳总结进行开发新药已成为研究热点。
