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The role of water molecules in the deacylation of acylated structures of class A beta-lactamase. 水分子在A类β -内酰胺酶酰基化结构的去酰化中的作用。
Drug design and discovery Pub Date : 1999-08-01
M Ishiguro, S Imajo
{"title":"The role of water molecules in the deacylation of acylated structures of class A beta-lactamase.","authors":"M Ishiguro,&nbsp;S Imajo","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Molecular dynamics simulation of the penicillin- and penem-acylated enzymes reveals that the conformational flexibility of the acyl moieties in the binding cleft and the conformational change of the acyl moieties are crucial for deacylation. The water molecule adjacent to the Glu 166 residue is not the nucleophile for deacylation, but construction of a model of the oxyanion tetrahedral intermediate suggested a plausible role of the water molecule as a proton donor for the oxyanion to facilitate the deacylation.</p>","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"16 2","pages":"131-43"},"PeriodicalIF":0.0,"publicationDate":"1999-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21394944","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
Syntheses and SH-enzyme inhibitory activities of new epoxysuccinic acid piperazine derivatives against mu-calpain and cathepsin B. 新型环氧琥珀酸哌嗪衍生物的合成及其对钙蛋白酶和组织蛋白酶B的sh酶抑制活性。
Drug design and discovery Pub Date : 1999-08-01
J Inoue, Y Yoshida, M Nakamura, Y S Cui, Y Nagao
{"title":"Syntheses and SH-enzyme inhibitory activities of new epoxysuccinic acid piperazine derivatives against mu-calpain and cathepsin B.","authors":"J Inoue,&nbsp;Y Yoshida,&nbsp;M Nakamura,&nbsp;Y S Cui,&nbsp;Y Nagao","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>New chiral epoxysuccinic acid derivatives 5 approximately 23 bearing various amino acids and N-substituted piperazines were synthesized to evaluate their inhibitory activities against mu-calpain and cathepsin B. After screening these compounds, 1-[(2S,3S)-epoxysuccinyl-L-leucyl]-4-(2-chlorophenyl)piperazine 9 proved to exhibit fairly strong inhibitory activity against both cysteine proteases. L-Valyl derivative 19 exhibited selective inhibitory activity against cathepsin B in comparison with that against mu-calpain.</p>","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"16 2","pages":"165-9"},"PeriodicalIF":0.0,"publicationDate":"1999-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21394819","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
Three-dimensional quantitative structure-activity relationships (3D-QSAR) of antidiabetic thiazolidinediones. 抗糖尿病噻唑烷二酮的三维定量构效关系(3D-QSAR)。
Drug design and discovery Pub Date : 1999-08-01
Y Kurogi
{"title":"Three-dimensional quantitative structure-activity relationships (3D-QSAR) of antidiabetic thiazolidinediones.","authors":"Y Kurogi","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Thiazolidine-2,4-diones (TZDs) are novel insulin resistance releasing compounds that serve as orally active antidiabetic agents. Many TZDs have been synthesized and evaluated by in vivo screening for over 20 years. Recently, TZDs have been found to be selective agonists of peroxisome proliferator-activated receptor-y (PPAR-gamm), which is believed to work in the regulation of insulin resistance. This paper reports our efforts for the pharmacophore modeling study through 3D (three-dimensional) structure-activity relationship of TZDs to gain an insight into their molecular mechanism as well as the relation between antihyperglycemic and PPAR-gamma agonistic activities. The modeling study was carried out by conformational analysis along with the Apex-3D QSAR method to identify molecular features common to a series of 7 selected TZDs. Although the number of compounds included in the study was rather low, the variations in the activities were nicely elucidated with 3D-site specific physiochemical parameters significantly.</p>","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"16 2","pages":"109-18"},"PeriodicalIF":0.0,"publicationDate":"1999-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21394942","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
Synthesis and biological evaluation of carbocyclic analogues of lipid X: new nonpolar antagonists of LPS induced TNF production. 脂质X的碳环类似物的合成和生物学评价:LPS诱导TNF生成的新非极性拮抗剂。
Drug design and discovery Pub Date : 1999-07-01
S Augy-Dorey, D C Billington, J A Camara, S D Gero, I Sagnard, B Quiclet-Sire, D Ghezzi
{"title":"Synthesis and biological evaluation of carbocyclic analogues of lipid X: new nonpolar antagonists of LPS induced TNF production.","authors":"S Augy-Dorey,&nbsp;D C Billington,&nbsp;J A Camara,&nbsp;S D Gero,&nbsp;I Sagnard,&nbsp;B Quiclet-Sire,&nbsp;D Ghezzi","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>We have synthesised a number of analogues of lipid X, a precursor in the biosynthesis of LPS, some of which exhibit marked antagonism of LPS induced TNF production in vivo. These compounds provide new non-polar leads in the search for a therapy for endotoxic shock.</p>","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"16 1","pages":"41-8"},"PeriodicalIF":0.0,"publicationDate":"1999-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21329964","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
A comparison of backpropagation and generalized-regression genetic-neural network models. 反向传播与广义回归遗传神经网络模型的比较。
Drug design and discovery Pub Date : 1999-07-01
P P Mager, R Reinhardt
{"title":"A comparison of backpropagation and generalized-regression genetic-neural network models.","authors":"P P Mager,&nbsp;R Reinhardt","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The results of the backpropagation (BP) and generalized-regression genetic-neural (GRGN) network were compared using a series of nonpeptide arginine vasopressin VI antagonists. It was shown that both approaches are equivalent with respect to the recognition process while the BP network is superior over GRGN if the sample sizes are lowered by cross-validation.</p>","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"16 1","pages":"49-53"},"PeriodicalIF":0.0,"publicationDate":"1999-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21329965","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
Studies of molecular pharmacophore/receptor models for GABAA/BzR subtypes: binding affinities of symmetrically substituted pyrazolo[4,3-c]quinolin-3-ones at recombinant alpha x beta 3 gamma 2 subtypes and quantitative structure-activity relationship studies via a comparative molecular field analysis. GABAA/BzR亚型的分子药效团/受体模型研究:对称取代吡唑啉[4,3-c]喹啉-3- 1在重组α x β 3 γ 2亚型上的结合亲和力及通过比较分子场分析的定量构效关系研究
Drug design and discovery Pub Date : 1999-07-01
X He, Q Huang, S Yu, C Ma, R McKernan, J M Cook
{"title":"Studies of molecular pharmacophore/receptor models for GABAA/BzR subtypes: binding affinities of symmetrically substituted pyrazolo[4,3-c]quinolin-3-ones at recombinant alpha x beta 3 gamma 2 subtypes and quantitative structure-activity relationship studies via a comparative molecular field analysis.","authors":"X He,&nbsp;Q Huang,&nbsp;S Yu,&nbsp;C Ma,&nbsp;R McKernan,&nbsp;J M Cook","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>A series of symmetrically substituted pyrazoloquinolinones was synthesized to probe the BzR binding site of different GABAA/Bz receptor subtypes. The affinities of the ligands for different BzR subtypes have been determined by radioligand binding assays on 5 distinct recombinant GABAA receptor isoforms [alpha x beta 3 gamma 2 (x = 1,2,3,5, or 6)]. Most of the ligands synthesized exhibited potent biological activity in vitro. Among them, 3 ligands exhibited enhanced affinity for the alpha 2 beta 3 gamma 2 subtype in comparison to the other subtypes, six ligands demonstrated higher affinity for the alpha 3 beta 3 gamma 2 subtype, while 2 ligands showed some enhanced affinity for the alpha 5 beta 3 gamma 2 subtype. The remainder of the ligands exhibited relatively higher affinities at the alpha 1 containing subtype. To map out the steric and electronic differences between the benzodiazepine binding subtypes, a QSAR analysis by the method of Comparative Molecular Field Analysis (CoMFA) of each receptor subtypes was carried out.</p>","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"16 1","pages":"77-91"},"PeriodicalIF":0.0,"publicationDate":"1999-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21329967","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
Studies of molecular pharmacophore/receptor models for GABAA/benzodiazepine receptor subtypes: binding affinities of substituted beta-carbolines at recombinant alpha x beta 3 gamma 2 subtypes and quantitative structure-activity relationship studies via a comparative molecular field analysis. GABAA/苯二氮卓受体亚型的分子药效团/受体模型研究:通过比较分子场分析取代β -碳卡啉在重组α x β 3 γ 2亚型上的结合亲和力和定量构效关系研究。
Drug design and discovery Pub Date : 1999-07-01
Q Huang, E D Cox, T Gan, C Ma, D W Bennett, R M McKernan, J M Cook
{"title":"Studies of molecular pharmacophore/receptor models for GABAA/benzodiazepine receptor subtypes: binding affinities of substituted beta-carbolines at recombinant alpha x beta 3 gamma 2 subtypes and quantitative structure-activity relationship studies via a comparative molecular field analysis.","authors":"Q Huang,&nbsp;E D Cox,&nbsp;T Gan,&nbsp;C Ma,&nbsp;D W Bennett,&nbsp;R M McKernan,&nbsp;J M Cook","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Binding affinities of a series of 44 beta-carbolines with various substituents at the 3-, 4-, 6- and 7-positions are reported at 5 distinct recombinant GABAA/benzodiazepine receptor (BzR) subtypes [alpha x beta 3 gamma 2 (x = 1-3, 5, 6)]. Many of these ligands displayed better selectivity for the alpha 1 containing GABAA isoform. The most selective BCCT 2 and SPH 195 (17) displayed potent affinity (Ki = 0.72 and 7.2 nM for the alpha 1 beta 3 gamma 2 receptor subtype, respectively) and an overall selectivity of 20 and 23 fold, respectively, for the alpha 1 beta 3 gamma 2 receptor subtype. These are the most selective ligands in vitro for the alpha 1 containing GABAA/Bz receptor isoform reported to date to our knowledge. QSAR studies of these ligands for each receptor subtype have been carried out via a Comparative Molecular Field Analysis (CoMFA) and an included volume analysis. Geometries and charge distributions of these ligands have been optimized using ab initio methods (J. Med. Chem., 1992, 35, 4001-4010). Active conformations of flexible 3-alkoxylated beta-carbolines have been examined via a CoMFA approach. QSAR studies via CoMFA support the previous hypothesis that beta-carbolines with different intrinsic activities may follow an alternative alignment rule when they bind into the pharmacophore/receptor site of the BzR. Examination of binding affinities of beta-carbolines by this modeling strategy has established some of the differences, in particular, topologic differences between the lipophilic pockets in the alpha 1 beta 3 gamma 2, alpha 2 beta 3 gamma 2, alpha 3 beta 3 gamma 2, alpha 5 beta 3 gamma 2 and alpha 6 beta 3 gamma 2 subtypes as well as some of the similarities among the pharmacophore/receptor models of these five distinct GABAA/Bz receptor subtypes.</p>","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"16 1","pages":"55-76"},"PeriodicalIF":0.0,"publicationDate":"1999-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21329966","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
Rational drug design using trypanothione reductase as a target for anti-trypanosomal and anti-leishmanial drug leads. 以锥虫硫酮还原酶为靶点的抗锥虫和抗利什曼原虫药物先导物的合理药物设计。
Drug design and discovery Pub Date : 1999-07-01
S E Austin, M O Khan, K T Douglas
{"title":"Rational drug design using trypanothione reductase as a target for anti-trypanosomal and anti-leishmanial drug leads.","authors":"S E Austin,&nbsp;M O Khan,&nbsp;K T Douglas","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The parasite enzyme trypanothione reductase has been used as a target for rational drug design against trypanosomiasis and leishmaniasis in a number of laboratories. In this article the biochemical basis for its selection as a target is reviewed. The relevant structural aspects of the target are then compared with the homologous structure found in the mammalian hosts to indicate the molecular basis by which selective toxicity is likely to be achieved. An overview of known classes of inhibitors is provided, preparatory to a detailed coverage of approaches that have been taken to obtaining strong, selective inhibitors and the steps taken in the process of the initial discovery of tricyclic structures by interactive molecular graphics ligand design are outlined. Recent quantitative docking approaches which have been applied to this system are also described. Finally, the biological data of the activity against the various parasitic forms in vitro and in vivo are summarised.</p>","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"16 1","pages":"5-23"},"PeriodicalIF":0.0,"publicationDate":"1999-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21330107","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
Inhibition of dihydrofolate reductases from Toxoplasma gondii, Pneumocystis carinii, and rat liver by rotationally restricted analogues of pyrimethamine and metoprine. 乙胺嘧啶和甲托林旋转限制性类似物对刚地弓形虫、卡氏肺囊虫和大鼠肝脏中二氢叶酸还原酶的抑制作用。
Drug design and discovery Pub Date : 1999-07-01
A Rosowsky, S F Queener, V Cody
{"title":"Inhibition of dihydrofolate reductases from Toxoplasma gondii, Pneumocystis carinii, and rat liver by rotationally restricted analogues of pyrimethamine and metoprine.","authors":"A Rosowsky,&nbsp;S F Queener,&nbsp;V Cody","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Twenty-one conformationally restricted tricyclic pyrimethamine and metoprine analogues with one or two chlorine atoms, or other substituents, at different positions of the phenyl ring were tested for potency and species selectivity against dihydrofolate reductase (DHFR) from Toxoplasma gondii, Pneumocystis carinii, and rat liver. Heterocyclic systems studied included indeno[2,1-d]pyrimidines, benzo[f]quinazolines, and benzo[3,4]cyclohepta[1,2-d]pyrimidines. All but one of the analogues were more potent against T. gondii and rat liver DHFR than against P. carinii DHFR, and those with a one-carbon (CH2) bridge were generally less potent than those with a two-carbon (CH2CH2, CH=CH) or three-carbon (CH2CH2CH2) bridge. Although a number of compounds with a two- and three-carbon bridge were more potent than pyrimethamine against P. carinii DHFR, and especially T. gondii DHFR, none of them were selective for the P. carinii versus the mammalian enzyme, and only those with a one-carbon bridge showed selectivity approaching that of pyrimethamine for the T. gondii enzyme. Computer-simulated docking into the active site pocket of P. carinii and human DHFR suggested that, as a group, the rotationally restricted tricyclic structures are at a disadvantage relative to pyrimethamine and metoprine, in that torsional relief of unfavorable steric interactions between the chlorine atoms and two critical serine and threonine residues in the active site is prevented by the bridge.</p>","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"16 1","pages":"25-40"},"PeriodicalIF":0.0,"publicationDate":"1999-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21330108","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
Review of the molecular modelling studies of the cytochrome P-450 estrogen synthetase enzyme, aromatase. 细胞色素P-450雌激素合成酶、芳香化酶的分子模拟研究综述。
Drug design and discovery Pub Date : 1998-10-01
S Ahmed
{"title":"Review of the molecular modelling studies of the cytochrome P-450 estrogen synthetase enzyme, aromatase.","authors":"S Ahmed","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The biosynthesis of the family of female hormones, the estrogens, is mediated by the cytochrome P-450 based enzyme Aromatase (AR), an enzyme which has been the focus of extensive research for some time and has resulted in the synthesis of numerous inhibitory compounds with varying structural properties. The crystal structure of this membrane-bound enzyme has not been determined, although that of the bacterial P-450 camphor hydroxylase enzyme has, and the latter has been used for homology modelling of AR and other related enzymes. Several workers have attempted to obtain an approximate model of the active site of AR through the use of various molecular modelling techniques using inhibitors of this enzyme, as well as a combination of experiments involving active site mutagenesis of specific areas of the P-450 backbone together with molecular modelling. In this report these studies are reviewed. In summary, although the crystal structure of AR has yet to be determined, the use of molecular modelling studies has provided useful information in the design and synthesis of its inhibitors.</p>","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"15 4","pages":"239-52"},"PeriodicalIF":0.0,"publicationDate":"1998-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21406422","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
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