Drug design and discovery最新文献

In vitro and in vivo activities of acylated derivatives of isoniazid against mycobacterium tuberculosis. 异烟肼酰化衍生物抗结核分枝杆菌的体内外活性研究。

Drug design and discovery Pub Date : 2003-01-01

Michael J Hearn, Michael H Cynamon

{"title":"In vitro and in vivo activities of acylated derivatives of isoniazid against mycobacterium tuberculosis.","authors":"Michael J Hearn, Michael H Cynamon","doi":"","DOIUrl":"","url":null,"abstract":"Enzymatic acylation of the antitubercular isoniazid (INH) by N-acetyl transferases reduces the therapeutic effectiveness of the drug. Because it represents a major metabolic pathway for INH in human beings, such acetylation has serious consequences for tuberculosis treatment regimens. Among patients in whom this process is efficient, the \"rapid acetylators,\" the resultant chronic underdosing of INH may give rise to the development of resistance, as well as inadequate therapy. Not much work has been done previously to characterize the antitubercular properties of other N2-acylisoniazids. In order to address the fundamental issue of the activities of these acylated derivatives of INH, a number of such compounds 1a-f were chemically synthesized for investigation by a method providing good yield and purity. In experiments in vitro against Mycobacterium tuberculosis, these compounds displayed minimum inhibitory concentration (MIC) values between several fold and several hundred fold greater than that of INH itself, on a molar basis, with some of the more active compounds having higher calculated values of log P. Among these derivatives, compound 1b, closely homologous to the INH metabolite 1a, N2-acetylisoniazid, provided unexpected protection in tuberculosis-infected mice. The authors conclude that such close structural congeners of metabolites of INH may serve as significant leads in antitubercular drug discovery and in the exploration of the mode of action of INH.","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"18 4","pages":"103-8"},"PeriodicalIF":0.0,"publicationDate":"2003-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24820728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structure-based design of novel inhibitors of 3-deoxy-D-manno-octulosonate 8-phosphate synthase. 新型3-脱氧-d -甘露糖醛酸8-磷酸合酶抑制剂的结构设计。

Drug design and discovery Pub Date : 2003-01-01

Xingjue Xu, Jian Wang, Claude Grison, Sylvian Petek, Philippe Coutrot, Matthew R Birck, Ronald W Woodard, Domenico L Gatti

引用次数: 0

Structure-based design of novel inhibitors of 3-deoxy-D-manno-octulosonate 8-phosphate synthase. 新型3-脱氧-d -甘露糖醛酸8-磷酸合酶抑制剂的结构设计。

Drug design and discovery Pub Date : 2003-01-01 DOI: 10.1080/10559610290271787

Xingjue Xu, Jian Wang, C. Grison, Sylvian Petek, P. Coutrot*, M. Birck, R. Woodard, D. Gatti

引用次数: 16

HIV-1 reverse transcriptase variants: molecular modeling of Y181C, V106A, L100I, and K103N mutations with nonnucleoside inhibitors using Monte Carlo simulations in combination with a linear response method. HIV-1逆转录酶变异体:使用蒙特卡罗模拟结合线性响应方法的非核苷抑制剂对Y181C, V106A, L100I和K103N突变进行分子建模。

Drug design and discovery Pub Date : 2003-01-01 DOI: 10.3109/10559610390484203

Marilyn B Kroeger Smith, Sandra Ruby, Stanislav Horouzhenko, Bryan Buckingham, Julia Richardson, Ina Puleri, Emily Potts, William L Jorgensen, Edward Arnold, Wanyi Zhang, Stephen H Hughes, Christopher J Michejda, Richard H Smith

{"title":"HIV-1 reverse transcriptase variants: molecular modeling of Y181C, V106A, L100I, and K103N mutations with nonnucleoside inhibitors using Monte Carlo simulations in combination with a linear response method.","authors":"Marilyn B Kroeger Smith, Sandra Ruby, Stanislav Horouzhenko, Bryan Buckingham, Julia Richardson, Ina Puleri, Emily Potts, William L Jorgensen, Edward Arnold, Wanyi Zhang, Stephen H Hughes, Christopher J Michejda, Richard H Smith","doi":"10.3109/10559610390484203","DOIUrl":"https://doi.org/10.3109/10559610390484203","url":null,"abstract":"The energies and physical descriptors for the binding of 21 novel 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-benzimidazole (BPBI) analogs to HIV-1 reverse transcriptase (RT) variants Y181C, L100I, V106A, and K103N have been determined using Monte Carlo (MC) simulations. The crystallographic structure of the lead compound, 4-methyl BPBI, was used as a starting point to model the inhibitors in both the mutant bound and the unbound states. The energy terms and physical descriptors obtained from the calculations were reasonably correlated with the respective experimental EC50 values for the inhibitors against the various mutant RTs. Using the linear response correlations from the calculations, 2 novel BPBI inhibitors have been designed and simulations have been carried out. The results show the computed deltaG(binding) values match the experimental data for the analogs. Given the ongoing problem with drug resistance, the ability to predict the activity of novel analogs against variants prior to synthesis is highly advantageous.","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"18 4","pages":"151-63"},"PeriodicalIF":0.0,"publicationDate":"2003-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3109/10559610390484203","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24821945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

3D-QSAR studies of some [[1-aryl(or benzyl)-1-(benzenesulphonamido)methyl] phenyl] alkanoic acid derivatives as thromboxane A2 receptor antagonists. 一些[[1-芳基(或苄基)-1-(苯磺酸胺)甲基]苯基]烷酸衍生物作为血栓素A2受体拮抗剂的3D-QSAR研究。

Drug design and discovery Pub Date : 2003-01-01 DOI: 10.3109/10559610290252869

K. V. Sairam, J. Sarma, G. Desiraju

引用次数: 1

Synthesis and three-dimensional quantitative structure-activity relationship analysis of H3 receptor antagonists containing a neutral heterocyclic polar group. 含中性杂环极性基团H3受体拮抗剂的合成及三维定量构效关系分析。

Drug design and discovery Pub Date : 2003-01-01 DOI: 10.1080/10559610290249539

S. Rivara, M. Mor, F. Bordi, Claudia Silva, V. Zuliani, F. Vacondio, G. Morini, P. Plazzi, P. Carrupt, B. Testa

{"title":"Synthesis and three-dimensional quantitative structure-activity relationship analysis of H3 receptor antagonists containing a neutral heterocyclic polar group.","authors":"S. Rivara, M. Mor, F. Bordi, Claudia Silva, V. Zuliani, F. Vacondio, G. Morini, P. Plazzi, P. Carrupt, B. Testa","doi":"10.1080/10559610290249539","DOIUrl":"https://doi.org/10.1080/10559610290249539","url":null,"abstract":"Three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was applied to a series of H(3) receptor antagonists characterized by an imidazole ring, an alkyl spacer, and a heterocyclic polar moiety containing an imidazole or a thiazole ring, with a view to investigate the requirements for H(3) receptor affinity on rat cortex membranes. The compounds were aligned based on the hypothesis that the presence of a H-bond donor group in the polar portion of the molecule can increase H(3) receptor affinity. The 3D-QSAR analysis, which was performed using both the CoMFA and CoMSIA protocols, revealed that the presence of a H-bond donor group is not statistically relevant for H(3) receptor affinity. Based on this result, another alignment was adopted that took into consideration the structural features common to all compounds, namely the imidazole ring and the N atom with a free lone pair in the polar portion. The 3D-QSAR models thus obtained showed that H(3) receptor affinity is modulated by the position and direction of the intermolecular interaction elicited by the polar group in the ligands.","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"33 1","pages":"65-79"},"PeriodicalIF":0.0,"publicationDate":"2003-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82174910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 6

Quantitative structure-activity relationship study on some azidopyridinyl neonicotinoid insecticides for their selective affinity towards the drosophila nicotinic receptor over mammalian alpha4beta2 receptor using electrotopological state atom index. 利用电拓扑态原子指数定量研究一些叠氮吡啶类新烟碱类杀虫剂对果蝇烟碱受体选择性亲和性优于哺乳动物α 4 β 2受体的构效关系。

Drug design and discovery Pub Date : 2003-01-01 DOI: 10.3109/10559610290249557

Bikash Debnath, Shovanlal Gayen, Sudip Kumar Naskar, Kunal Roy, Tarun Jha

引用次数: 17

Sulfonate Ester Hydroxamic Acids as Potent and Selective Inhibitors of TACE Enzyme 磺酸酯羟肟酸作为TACE酶的有效和选择性抑制剂

Drug design and discovery Pub Date : 2003-01-01 DOI: 10.1080/10559610390476473

J. Levin, M. Du

引用次数: 0

Conformational analysis of globomycin with a signal peptidase II inhibitory activity using molecular dynamics simulation. 具有信号肽酶II抑制活性的球霉素的分子动力学模拟构象分析。

Drug design and discovery Pub Date : 2003-01-01 DOI: 10.3109/10559610390450723

T. Kiho, Y. Iwata, H. Kogen, S. Miyamoto

引用次数: 1

Structural bioinformatics and QSAR analysis applied to the acetylcholinesterase and bispyridinium aldoximes. 结构生物信息学和QSAR分析应用于乙酰胆碱酯酶和双吡啶醛肟。

Drug design and discovery Pub Date : 2003-01-01 DOI: 10.3109/10559610390484168

P. Mager, A. Weber

{"title":"Structural bioinformatics and QSAR analysis applied to the acetylcholinesterase and bispyridinium aldoximes.","authors":"P. Mager, A. Weber","doi":"10.3109/10559610390484168","DOIUrl":"https://doi.org/10.3109/10559610390484168","url":null,"abstract":"The methods of bioinformatics, molecular modelling, and quantitative structure-activity relationships (QSARs) using regression and artificial neural network (ANN) analyses were applied to develop safer aldoxime antidotes against poisoning by organophosphorus (OP) agents with high, mean, and low aging rates. We start here from a molecular modelling of the mouse AChE at an atomistic level. Aim is to predict qualitatively the structural requirements of an aldoxime that shows an unique reactivating activity against the three classes of OPs. An antidotal action should occur by a three-site mechanism: the aldoxime groups of the first pyridinium ring should point towards the catalytic site, and the second pyridinium ring and its substituents should be anchored at the peripherical and anionic subsites. Based on this model, it is predicted that a suitable substituent is based on an arginine-like moiety. Then, an ANN-based QSAR analysis using a training set of aldoximes with known structure and activities was applied. Its input layer consisted of seven nodes: the group-membership descriptors that parameterize the type of the OP, the logarithms of the distribution coefficients at pH 7.4 and their squared term, the lowest unoccupied molecular orbital (LUMO) energies, the scaled molar refractions of the substituents, and their squared term. It was shown that the qualitative prediction made by molecular modelling can be quantified by an ANN prediction.","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"9 1","pages":"127-50"},"PeriodicalIF":0.0,"publicationDate":"2003-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73418112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 8