Seiji Hitaoka, Y. Shibata, Hiroshi Matoba, A. Kawano, M. Harada, Mustafizur Rahman, D. Tsuji, T. Hirokawa, K. Itoh, Tatsusada Yoshida, H. Chuman
Four human neuraminidases (hNEUs1–4) have been identified. Among them, hNEU1 has been studied extensively as a target for sialidosis. It has been desired to understand the biological functions of hNEU1 at the molecular and atomic levels. The three-dimensional structure of hNEU1 is not known at present. In the present work, we constructed a three-dimensional structure of hNEU1 by homology modeling, and then performed correlation analyses between observed and calculated free-energy changes (quantitative structure−activity relationship (QSAR) analyses), coupled with LERE (linear expression by representative energy terms) procedure using the modeled three-dimensional structure in order to confirm the validity of the modeled structure. The atomic coordinates of all atoms in the verified model of hNEU1 are available. The proposed structure of hNEU1 will be useful and helpful for further studies concerning the biological and chemical functions of hNEU1. The present article is one of continuous works derived from the one that won the CBI
{"title":"Modeling of Human Neuraminidase-1 and Its Validation by LERE-Correlation Analysis","authors":"Seiji Hitaoka, Y. Shibata, Hiroshi Matoba, A. Kawano, M. Harada, Mustafizur Rahman, D. Tsuji, T. Hirokawa, K. Itoh, Tatsusada Yoshida, H. Chuman","doi":"10.1273/CBIJ.13.30","DOIUrl":"https://doi.org/10.1273/CBIJ.13.30","url":null,"abstract":"Four human neuraminidases (hNEUs1–4) have been identified. Among them, hNEU1 has been studied extensively as a target for sialidosis. It has been desired to understand the biological functions of hNEU1 at the molecular and atomic levels. The three-dimensional structure of hNEU1 is not known at present. In the present work, we constructed a three-dimensional structure of hNEU1 by homology modeling, and then performed correlation analyses between observed and calculated free-energy changes (quantitative structure−activity relationship (QSAR) analyses), coupled with LERE (linear expression by representative energy terms) procedure using the modeled three-dimensional structure in order to confirm the validity of the modeled structure. The atomic coordinates of all atoms in the verified model of hNEU1 are available. The proposed structure of hNEU1 will be useful and helpful for further studies concerning the biological and chemical functions of hNEU1. The present article is one of continuous works derived from the one that won the CBI","PeriodicalId":40659,"journal":{"name":"Chem-Bio Informatics Journal","volume":"687 1","pages":"30-44"},"PeriodicalIF":0.3,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89543709","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}
Initial state-independent phenotypic diversification will be a powerful tool for directing cells to multiple phenotypes in practical situation, in which initial cellular states are unknown. In this study, we designed Symmetric Diversity Generator (SDG) for the initial state-independent phenotypic diversification, in which homogenous cells diversify into two phenotypes and the ratio of the phenotypes do not depend on the initial cellular state. The SDG consists of two mechanisms: an intracellular mutual inhibition by repressors and an intercellular activation of the repressor productions by intercellular activators that are expected to compensate imbalance of repressor concentrations and of intercellular activator concentrations. We computationally evaluated the initial state dependence of the SDG in terms of the ratio of the two phenotypes after the diversification, and found the SDG still has initial state dependence. For lower dependence, we designed two kinds of symmetric diversity generator focusing on degradation rate of activators and responsiveness of repressor productions to transcription factors, activators and repressors. Our computational evaluation suggests that the latter approach is much more promising than the former one because the intercellular activators can compensate the imbalance of the transcription factors in advance of response of repressor productions. The former approach would be used for improvement of robustness of other synthetic genetic circuits already designed.
{"title":"Design strategy for an initial state-independent diversity generator","authors":"Ryoji Sekine, D. Kiga, M. Yamamura","doi":"10.1273/CBIJ.12.39","DOIUrl":"https://doi.org/10.1273/CBIJ.12.39","url":null,"abstract":"Initial state-independent phenotypic diversification will be a powerful tool for directing cells to multiple phenotypes in practical situation, in which initial cellular states are unknown. In this study, we designed Symmetric Diversity Generator (SDG) for the initial state-independent phenotypic diversification, in which homogenous cells diversify into two phenotypes and the ratio of the phenotypes do not depend on the initial cellular state. The SDG consists of two mechanisms: an intracellular mutual inhibition by repressors and an intercellular activation of the repressor productions by intercellular activators that are expected to compensate imbalance of repressor concentrations and of intercellular activator concentrations. We computationally evaluated the initial state dependence of the SDG in terms of the ratio of the two phenotypes after the diversification, and found the SDG still has initial state dependence. For lower dependence, we designed two kinds of symmetric diversity generator focusing on degradation rate of activators and responsiveness of repressor productions to transcription factors, activators and repressors. Our computational evaluation suggests that the latter approach is much more promising than the former one because the intercellular activators can compensate the imbalance of the transcription factors in advance of response of repressor productions. The former approach would be used for improvement of robustness of other synthetic genetic circuits already designed.","PeriodicalId":40659,"journal":{"name":"Chem-Bio Informatics Journal","volume":"13 1","pages":"39-49"},"PeriodicalIF":0.3,"publicationDate":"2012-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90229403","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}
Y. Tada, I. Yamawaki, S. Ueda, H. Matsumoto, N. Matsuura, M. Yasumoto, A. Koda, M. Hori
In the development of the anti-allergic drug Suplatast Tosilate (IPD-1151T) we have reported the QSAR analysis using only the calculated values, because the few logK values of sulfonium compounds had been measured till then. In this study, we measured the logKTLC value of sulfonium compounds by using octylsililated silicagel plate (Merck HPTLC RP-8 F254S). The logKTLC values of the optimized compounds 52 and 67 (Suplatast Tosilate) of dimethylsulfonium p-toluenesulfonates derivatives were 0.07 and 0.06, respectively. Therefore, it was found that the desirable logKTLC value of the sulfonium compound was approximately zero as the anti-allergic drug.
{"title":"Optimal Lipophilicity of Sulfonium p-Toluenesulfonate as Anti-allergic Drug","authors":"Y. Tada, I. Yamawaki, S. Ueda, H. Matsumoto, N. Matsuura, M. Yasumoto, A. Koda, M. Hori","doi":"10.1273/CBIJ.12.25","DOIUrl":"https://doi.org/10.1273/CBIJ.12.25","url":null,"abstract":"In the development of the anti-allergic drug Suplatast Tosilate (IPD-1151T) we have reported the QSAR analysis using only the calculated values, because the few logK values of sulfonium compounds had been measured till then. In this study, we measured the logKTLC value of sulfonium compounds by using octylsililated silicagel plate (Merck HPTLC RP-8 F254S). The logKTLC values of the optimized compounds 52 and 67 (Suplatast Tosilate) of dimethylsulfonium p-toluenesulfonates derivatives were 0.07 and 0.06, respectively. Therefore, it was found that the desirable logKTLC value of the sulfonium compound was approximately zero as the anti-allergic drug.","PeriodicalId":40659,"journal":{"name":"Chem-Bio Informatics Journal","volume":"1 1","pages":"25-38"},"PeriodicalIF":0.3,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89430785","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}
S. Yoshida, D. Murata, S. Taira, Keita Iguchi, M. Takano, Yoshiyuki Nakano, K. Minakuchi
Biopharmaceutical monoclonal antibodies (Mabs) show different chromatographic behaviors in the elution step on protein A chromatography, although Mabs have similar three-dimensional structures. It is well known that interactions of conventional protein A to the V H 3 subfamily variable region negatively affect Mabs elution properties. The mutation G29A is known to weaken this binding, although not always sufficiently. We designed novel protein A mutations, S33E and D36R, by a computer-aided evaluation based on the three-dimensional structure. These mutations are expected to not only eliminate protein A binding to the variable region of Mabs but also to maintain its alkaline stability, which is required for effective CIP (Clean in place) of the protein A affinity matrix. In view of the superior potential of C domain, an in vitro study was performed with the G29A mutant of C domain (C-G29A) as a model protein. Both pentameric C domain mutants (C-G29A/S33E.5d and C-G29A/D36R.5d) showed little binding ability to the V H 3 subfamily variable region of Mabs by BIACORE analysis. We used a C-G29A/S33E.5d-immobilized matrix to confirm that the elution profile of Mabs belonging to the V H 3 subfamily at pH 3.5 was significantly improved. This matrix also showed almost the same alkaline stability as did the C-G29A.5d-immobilized matrix. The engineered protein A ligand, whose binding ability to the variable region is completely eliminated, would enable the separation of Fab fragments in flow-through fractions from Mab digestions. Rational design by a computer-aided evaluation should enhance the efficiency of protein ligand engineering. -9.0 T (Thr) +23.9 (-3.3) +0.9 +15.4 (-9.9) -5.0 The results of the mutations at residue Ser-33 or Asp-36 of C domain are shown. As for the complex, another result by adjusting the relatively high dielectric constant is shown in parentheses ( ). The negative G of the mutants (Fab complex or free-state) indicate better thermostability than the case of the respective wild type. Hence, in this study, the positive G complex is preferable in a complex to eliminate the binding to Fab, while the negative G free is preferable in the free
生物制药单克隆抗体(mab)在蛋白A层析的洗脱步骤中表现出不同的色谱行为，尽管单克隆抗体具有相似的三维结构。众所周知，常规蛋白A与vh3亚家族可变区域的相互作用会对mab的洗脱性能产生负面影响。已知突变G29A会削弱这种结合，尽管并不总是充分削弱。我们通过基于三维结构的计算机辅助评估设计了新的蛋白A突变S33E和D36R。预计这些突变不仅可以消除蛋白A与单克隆抗体可变区域的结合，还可以保持其碱性稳定性，这是蛋白A亲和基质有效CIP (Clean in place)所必需的。鉴于C结构域的优越潜力，我们以C结构域的G29A突变体(C-G29A)作为模型蛋白进行了体外研究。这两个五聚体C结构域突变体(C- g29a /S33E)。经BIACORE分析，5d和C-G29A/D36R.5d)对单克隆抗体的vh3亚家族可变区结合能力较弱。我们使用的是C-G29A/S33E。5d-固定化基质，证实在pH 3.5下，vh3亚家族单克隆抗体的洗脱谱明显改善。该基质也表现出与C-G29A几乎相同的碱性稳定性。5 d-immobilized矩阵。工程蛋白A配体与可变区域的结合能力被完全消除，将使单抗消化的流动组分中Fab片段的分离成为可能。通过计算机辅助评价进行合理设计，可以提高蛋白质配体工程的效率。-9.0 T (Thr) +23.9 (-3.3) +0.9 +15.4 (-9.9) -5.0 C结构域Ser-33或Asp-36残基突变结果对于复合物，通过调整相对较高的介电常数得到的另一个结果如括号()所示。突变体(Fab复合体或自由态)的负G表明比各自的野生型具有更好的热稳定性。因此，在本研究中，为了消除与Fab的结合，配合物中首选正的G复合物，而游离物中首选负的G free复合物
{"title":"Rational design and engineering of protein A to obtain the controlled elution profile in monoclonal antibody purification","authors":"S. Yoshida, D. Murata, S. Taira, Keita Iguchi, M. Takano, Yoshiyuki Nakano, K. Minakuchi","doi":"10.1273/CBIJ.12.1","DOIUrl":"https://doi.org/10.1273/CBIJ.12.1","url":null,"abstract":"Biopharmaceutical monoclonal antibodies (Mabs) show different chromatographic behaviors in the elution step on protein A chromatography, although Mabs have similar three-dimensional structures. It is well known that interactions of conventional protein A to the V H 3 subfamily variable region negatively affect Mabs elution properties. The mutation G29A is known to weaken this binding, although not always sufficiently. We designed novel protein A mutations, S33E and D36R, by a computer-aided evaluation based on the three-dimensional structure. These mutations are expected to not only eliminate protein A binding to the variable region of Mabs but also to maintain its alkaline stability, which is required for effective CIP (Clean in place) of the protein A affinity matrix. In view of the superior potential of C domain, an in vitro study was performed with the G29A mutant of C domain (C-G29A) as a model protein. Both pentameric C domain mutants (C-G29A/S33E.5d and C-G29A/D36R.5d) showed little binding ability to the V H 3 subfamily variable region of Mabs by BIACORE analysis. We used a C-G29A/S33E.5d-immobilized matrix to confirm that the elution profile of Mabs belonging to the V H 3 subfamily at pH 3.5 was significantly improved. This matrix also showed almost the same alkaline stability as did the C-G29A.5d-immobilized matrix. The engineered protein A ligand, whose binding ability to the variable region is completely eliminated, would enable the separation of Fab fragments in flow-through fractions from Mab digestions. Rational design by a computer-aided evaluation should enhance the efficiency of protein ligand engineering. -9.0 T (Thr) +23.9 (-3.3) +0.9 +15.4 (-9.9) -5.0 The results of the mutations at residue Ser-33 or Asp-36 of C domain are shown. As for the complex, another result by adjusting the relatively high dielectric constant is shown in parentheses ( ). The negative G of the mutants (Fab complex or free-state) indicate better thermostability than the case of the respective wild type. Hence, in this study, the positive G complex is preferable in a complex to eliminate the binding to Fab, while the negative G free is preferable in the free","PeriodicalId":40659,"journal":{"name":"Chem-Bio Informatics Journal","volume":"40 1","pages":"1-13"},"PeriodicalIF":0.3,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76924682","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}
{"title":"Molecular Docking of Barbital Enantiomers to the Nicotinic Acetylcholine Receptor:Implications for the Mechanism of Anesthesia","authors":"T. Seto, Masayuki Ozaki, S. Nosaka","doi":"10.1273/CBIJ.12.14","DOIUrl":"https://doi.org/10.1273/CBIJ.12.14","url":null,"abstract":"全身麻酔薬の開発には分子標的、作用機序の解明が必要である。GABAA受容体は意識消失の重要な分子標的候補のひとつである。しかし、いまだ明確な分子標的の特定や作用部位の特性は未解決のままである。そこで、麻酔薬が作用し、詳細な3次元構造が分かっているGABAA受容体類似のモデル標的に着目し、対掌体麻酔薬の結合部位における適合性を調べれば、麻酔作用部位における麻酔薬の分子認識の特性が推定できると考えた。ニコチン性アセチルコリン受容体をモデルに使用して、amobarbital, 対掌体バルビタルisobarbital, pentobarbitalの結合様式(position, orientation, conformation)をドッキングシミュレーションの手法を用いて解明した。その結果、いずれのバルビツルもアゴニスト結合部位に結合し、対掌体RとSの結合はバルビツル酸環が重なる位置関係に結合した。バルビツル系麻酔薬の結合はバルビツル酸環が主な結合力になっていることがわかった。すなわち、対掌体麻酔薬といえども、受容体との主要な結合力がその不斉点を含まない部分構造に由来する場合、不斉炭素が存在してもその分子識別への寄与は相対的に小さくなることが判明した。本研究の範囲では、薬物と受容体の相互作用のほとんどがバルビツル酸環部分に依るものであり、側鎖アルキル鎖の不斉中心に起因する立体的な構造の差異は薬物結合力に大きな差異を生み出さなかった。麻酔作用部位でも同様に側鎖アルキル基の不斉点は結合力に大きな違いを生じない可能性がある。すなわち、バルビツル系麻酔薬の作用部位は対掌体の識別が弱い特性をもつと示唆された。","PeriodicalId":40659,"journal":{"name":"Chem-Bio Informatics Journal","volume":"58 1","pages":"14-24"},"PeriodicalIF":0.3,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82694822","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}
Yuki Kuriya, Shigemitsu Tanaka, G. Kobayashi, T. Hanai, M. Okamoto
Attempts were made to design and develop an analytical pipeline for identifying ways of increasing the production of a target metabolite that combine an optimized substrate-feeding schedule with a strategy for identifying and eliminating bottlenecks in metabolic pathways. As a case study, the proposed analytical pipeline was applied to acetone-butanol-ethanol fermentation by Clostridium bacteria, a process that has attracted considerable attention as a metabolic system capable of producing butanol, a possible biofuel.
{"title":"Development of an Analytical Pipeline for Optimizing Substrate Feeding and Eliminating Metabolic Bottlenecks","authors":"Yuki Kuriya, Shigemitsu Tanaka, G. Kobayashi, T. Hanai, M. Okamoto","doi":"10.1273/CBIJ.11.1","DOIUrl":"https://doi.org/10.1273/CBIJ.11.1","url":null,"abstract":"Attempts were made to design and develop an analytical pipeline for identifying ways of increasing the production of a target metabolite that combine an optimized substrate-feeding schedule with a strategy for identifying and eliminating bottlenecks in metabolic pathways. As a case study, the proposed analytical pipeline was applied to acetone-butanol-ethanol fermentation by Clostridium bacteria, a process that has attracted considerable attention as a metabolic system capable of producing butanol, a possible biofuel.","PeriodicalId":40659,"journal":{"name":"Chem-Bio Informatics Journal","volume":"5 1","pages":"1-23"},"PeriodicalIF":0.3,"publicationDate":"2011-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87518882","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}
Deoxynivalenol (DON) is a secondary metabolite that is generated by Fusarium species, which seriously affects both humans and livestock. Protein synthesis inhibition and ribotoxic stress, caused by induction of the mitogen activated protein kinase (MAPK) cascade, are thought to be responsible for the majority of DON toxicity. However, as DNA damage has also been reported, it is necessary to clarify all sources of toxicity. In this study, we conducted a DON exposure test using the PTC1 yeast mutant with disrupted MAPK-related genes, and observed gene expression changes using DNA microarray analysis. Our results indicated changes in the expression of genes associated with protein synthesis inhibition, as well as with DNA damage. At the same time, genes related to the synthesis of folic acid, a coenzyme in DNA synthesis, were inhibited. To complement the dysfunction of these genes, the growth media was supplemented with folic acid. As a result, the recovery of growth was confirmed, although it was a consistent effect and it did not reflect differences in susceptibility to DON toxicity.
{"title":"デオキシニバレノールがS. cerevisiae PTC1変異株に及ぼす遺伝子発現変化の解析","authors":"忠 鈴木, 岩橋 由美子","doi":"10.1273/CBIJ.11.41","DOIUrl":"https://doi.org/10.1273/CBIJ.11.41","url":null,"abstract":"Deoxynivalenol (DON) is a secondary metabolite that is generated by Fusarium species, which seriously affects both humans and livestock. Protein synthesis inhibition and ribotoxic stress, caused by induction of the mitogen activated protein kinase (MAPK) cascade, are thought to be responsible for the majority of DON toxicity. However, as DNA damage has also been reported, it is necessary to clarify all sources of toxicity. In this study, we conducted a DON exposure test using the PTC1 yeast mutant with disrupted MAPK-related genes, and observed gene expression changes using DNA microarray analysis. Our results indicated changes in the expression of genes associated with protein synthesis inhibition, as well as with DNA damage. At the same time, genes related to the synthesis of folic acid, a coenzyme in DNA synthesis, were inhibited. To complement the dysfunction of these genes, the growth media was supplemented with folic acid. As a result, the recovery of growth was confirmed, although it was a consistent effect and it did not reflect differences in susceptibility to DON toxicity.","PeriodicalId":40659,"journal":{"name":"Chem-Bio Informatics Journal","volume":"33 1","pages":"41-51"},"PeriodicalIF":0.3,"publicationDate":"2011-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80470658","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}
The problem decomposition strategy is a very efficient technique for the inference of S-system models of genetic networks. This strategy defines the inference of a genetic network consisting of N genes as N subproblems, each of which is a 2(N+1)-dimensional function optimization problem. Genetic networks made up of dozens genes can be analyzed with this strategy, though the computational cost in doing so remains quite high. In this study, we attempt to infer S-system models more efficiently by further dividing each 2(N+1)-dimensional subproblem into one (N+2)-dimensional problem and one (N+1)-dimensional problem. The subproblems are divided using the genetic network inference method based on linear programming machines (LPMs). Next, we propose a new method for estimating the S-system parameters by alternately solving the two divided problems. According to our experimental results, the proposed approach requires less than one-third of the time required by the original problem decomposition approach. Finally, we apply our approach to actual expression data from the bacterial SOS DNA repair system.
{"title":"遺伝子ネットワークのS-systemモデル同定のための効率的パラメータ推定：さらなる問題分割と交互最適化法の提案","authors":"周平 木村, 幸輝 松村, 岡田 眞里子","doi":"10.1273/CBIJ.11.24","DOIUrl":"https://doi.org/10.1273/CBIJ.11.24","url":null,"abstract":"The problem decomposition strategy is a very efficient technique for the inference of S-system models of genetic networks. This strategy defines the inference of a genetic network consisting of N genes as N subproblems, each of which is a 2(N+1)-dimensional function optimization problem. Genetic networks made up of dozens genes can be analyzed with this strategy, though the computational cost in doing so remains quite high. In this study, we attempt to infer S-system models more efficiently by further dividing each 2(N+1)-dimensional subproblem into one (N+2)-dimensional problem and one (N+1)-dimensional problem. The subproblems are divided using the genetic network inference method based on linear programming machines (LPMs). Next, we propose a new method for estimating the S-system parameters by alternately solving the two divided problems. According to our experimental results, the proposed approach requires less than one-third of the time required by the original problem decomposition approach. Finally, we apply our approach to actual expression data from the bacterial SOS DNA repair system.","PeriodicalId":40659,"journal":{"name":"Chem-Bio Informatics Journal","volume":"93 1","pages":"24-40"},"PeriodicalIF":0.3,"publicationDate":"2011-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74908362","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}
Bacterial RNA polymerase (RNAP) is the least popular target for antibiotics, and currently Rifampicin is only an approved drug for clinical use. However, RNAP is essential for bacterial growth and survival, and it can be a promising target for antimicrobial agents. Thus, we decided to search new antimicrobial agents for RNAP by virtual screening. When virtual screenings are performed, certain compounds repeatedly appears on hits covering a wide range of targets (frequently hitters). Also, the performance of hit generation is important factor in success of the virtual screening. Since we previously developed the optimized docking scores, we examined our scoring methods with rigorous removals of frequent hitters. We used two complex structures for RNAP, and also used two unrelated structures as negative controls to remove frequent hitters. Finally, we selected seven high-scored candidates from hits, and two of them showed the inhibition of Gram-positive bacteria by paper disk agar diffusion assay in vivo.
{"title":"Discovery of Novel Antimicrobial Agents Targeting the Bacterial RNA Polymerase by High-Throughput Virtual Screening","authors":"K. Onodera, T. Kawasaki, S. Kamijo","doi":"10.1273/CBIJ.11.52","DOIUrl":"https://doi.org/10.1273/CBIJ.11.52","url":null,"abstract":"Bacterial RNA polymerase (RNAP) is the least popular target for antibiotics, and currently Rifampicin is only an approved drug for clinical use. However, RNAP is essential for bacterial growth and survival, and it can be a promising target for antimicrobial agents. Thus, we decided to search new antimicrobial agents for RNAP by virtual screening. When virtual screenings are performed, certain compounds repeatedly appears on hits covering a wide range of targets (frequently hitters). Also, the performance of hit generation is important factor in success of the virtual screening. Since we previously developed the optimized docking scores, we examined our scoring methods with rigorous removals of frequent hitters. We used two complex structures for RNAP, and also used two unrelated structures as negative controls to remove frequent hitters. Finally, we selected seven high-scored candidates from hits, and two of them showed the inhibition of Gram-positive bacteria by paper disk agar diffusion assay in vivo.","PeriodicalId":40659,"journal":{"name":"Chem-Bio Informatics Journal","volume":"393 1","pages":"52-62"},"PeriodicalIF":0.3,"publicationDate":"2011-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79972862","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}
H. Kojo, Atsushi Doi, Y. Eguchi, T. Miyagishima, T. Taki, K. Makino, H. Terada
To elucidate the role of alterations to carbohydrate chains in cancer, we investigated changes in the expression of 107 glycogenes with the onset and progression of breast cancer by conducting an in silico analysis using GEO-registered data. A comparison between 43 breast tumors and paired normal controls (GSE15852) revealed significant changes in the expression of 24 glycogenes including the genes for 5 N-acetylgalactosaminyltransferases, 3 nucleotide sugar transporters, 3 asparagine-linked glycosylation-involved enzymes, 2 N-acetylglucosaminyl transferases, 2 fucosyltransferases, 2 sulfotransferases, 2 sulfatases, 1 glycosaminoglycan synthesis-involved enzyme, 1 glycosyltransferase, 1 glucosyltransferase, 1 sialyltransferase, and 1 N-acetylglucosaminidase. Furthermore, to clarify whether the expression of particular glycogenes changed dependent on the stage of cancer, we compared gene expression between preinvasive and invasive ductal carcinomas (GDS2045). The expression of 6 glycogenes exhibited significant changes in GDS2045. Notably, 3 of these genes were related to the sulfonation of carbohydrate chains. The upand down-regulated glycogenes were related to the synthesis of carbohydrate chains and the effects of changes in the expression of glycogenes on oncogenesis were discussed.
{"title":"Comprehensive In silico Analysis of the Expression of Glycogenes in Breast Cancer","authors":"H. Kojo, Atsushi Doi, Y. Eguchi, T. Miyagishima, T. Taki, K. Makino, H. Terada","doi":"10.1273/CBIJ.10.100","DOIUrl":"https://doi.org/10.1273/CBIJ.10.100","url":null,"abstract":"To elucidate the role of alterations to carbohydrate chains in cancer, we investigated changes in the expression of 107 glycogenes with the onset and progression of breast cancer by conducting an in silico analysis using GEO-registered data. A comparison between 43 breast tumors and paired normal controls (GSE15852) revealed significant changes in the expression of 24 glycogenes including the genes for 5 N-acetylgalactosaminyltransferases, 3 nucleotide sugar transporters, 3 asparagine-linked glycosylation-involved enzymes, 2 N-acetylglucosaminyl transferases, 2 fucosyltransferases, 2 sulfotransferases, 2 sulfatases, 1 glycosaminoglycan synthesis-involved enzyme, 1 glycosyltransferase, 1 glucosyltransferase, 1 sialyltransferase, and 1 N-acetylglucosaminidase. Furthermore, to clarify whether the expression of particular glycogenes changed dependent on the stage of cancer, we compared gene expression between preinvasive and invasive ductal carcinomas (GDS2045). The expression of 6 glycogenes exhibited significant changes in GDS2045. Notably, 3 of these genes were related to the sulfonation of carbohydrate chains. The upand down-regulated glycogenes were related to the synthesis of carbohydrate chains and the effects of changes in the expression of glycogenes on oncogenesis were discussed.","PeriodicalId":40659,"journal":{"name":"Chem-Bio Informatics Journal","volume":"1 1","pages":"100-110"},"PeriodicalIF":0.3,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76772754","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}
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