Chem-Bio Informatics Journal最新文献

{"title":"Universal Optimizations of Scoring Functions for Virtual Screening","authors":"K. Onodera, S. Kamijo","doi":"10.1273/CBIJ.10.85","DOIUrl":"https://doi.org/10.1273/CBIJ.10.85","url":null,"abstract":"Structure-based virtual screening is gaining popularity in drug discovery. A number of molecular docking programs and scoring functions have been developed in the community, but they had not fulfilled the demands for the improved accuracy, yet. In order to improve the accuracy, the consensus scoring method has been developed. It combines docking scores from various scoring functions without considering characteristics of the docking scores. In this study, we adopted the concepts of the consensus scoring, and improved the docking score from each docking programs, DOCK, FRED or GOLD, for virtual screening. Instead using simple sum of score components in those docking scores, weight factors of the score components were introduced and adjusted for better predictions of active ligands during virtual screening. Several optimization processes were tested to find the best optimization methods of the docking scores using a wide variety of 113 target proteins with over 2000 diverse decoys. Finally, the optimizations improved the chance to discover the active ligands by up to 52.4% (e.g. from 36.8% to 56.1% using GOLD) for the test set. Additionally, the combination of the optimized scores using GOLD and FRED improved success rate in the test set by 77.2%, and approximately 70% of ligands for target proteins were predictable in the test set with 20 times enrichment.","PeriodicalId":40659,"journal":{"name":"Chem-Bio Informatics Journal","volume":null,"pages":null},"PeriodicalIF":0.3,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72586206","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":"Gene expression profile of MAP kinase PTC1 mutant exposed to Aflatoxin B1: dysfunctions of gene expression in glucose utilization and sphingolipid metabolism","authors":"Tadahiro Suzuki, Y. Iwahashi","doi":"10.1273/CBIJ.9.94","DOIUrl":"https://doi.org/10.1273/CBIJ.9.94","url":null,"abstract":"Aflatoxin B1 (AFB1) is a harmful and cancer-causing mycotoxin generated by Aspergillus flavus. Its mechanism of toxicity has not been fully clarified and further research is required. In this study, we attempted to further clarify aflatoxin B1 toxicity using the results of S. cerevisiae gene expression analysis. In a Ser/Thr phosphatase 2C disruptant (ptc1Δ) with weakened activity of anti-toxic components (cell wall and membrane), the addition of low concentrations of sodium dodecyl sulfate resulted in elevated susceptibility to AFB1. From the microarray results, expression changes in DNA synthesis or repair, sphingolipid metabolism, glucose metabolism, and cell wall-related genes were well detected. Our results indicate that AFB1 causes sphingolipid metabolism disorder, leading to dysfunction in signal secretion and inhibition of efficient glucose metabolism, which supplies the materials for cell wall proteins and cellular components, resulting in repression of the stress response to external toxicants.","PeriodicalId":40659,"journal":{"name":"Chem-Bio Informatics Journal","volume":null,"pages":null},"PeriodicalIF":0.3,"publicationDate":"2009-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1273/CBIJ.9.94","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72421047","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":"Identification of the Dual Action Antihypertensive Drugs Using TFS-Based Support Vector Machines","authors":"Kentaro Kawai, Yoshimasa Takahashi","doi":"10.1273/CBIJ.10.E_1","DOIUrl":"https://doi.org/10.1273/CBIJ.10.E_1","url":null,"abstract":"Recently, many concerns are paid for dual action drugs such as ACE/NEP dual inhibitors which have two different biological activities. To identify multiple active drugs by supervised learning approach, a multi-label classification technique is required. In the present work, we investigated the classification of antihypertensive drugs including ACE/NEP dual inhibitors using support vector machines (SVMs). Biological activity data of the drugs were taken from the MDDR database and they were employed for the computational trial for the training of the SVM classifiers. Structural feature representation of each drug molecule was based on topological fragment spectra (TFS) method. The obtained classifiers were tested for finding ACE/NEP dual inhibitors. The result suggests that the TFS-based SVM classifiers are useful for finding multiple active drugs such as ACE/NEP dual inhibitors.","PeriodicalId":40659,"journal":{"name":"Chem-Bio Informatics Journal","volume":null,"pages":null},"PeriodicalIF":0.3,"publicationDate":"2009-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86329714","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":"Calculation of fraction of dose absorbed: comparison between analytical solution based on one compartment steady state concentration approximation and dynamic seven compartment model","authors":"K. Sugano","doi":"10.1273/CBIJ.9.75","DOIUrl":"https://doi.org/10.1273/CBIJ.9.75","url":null,"abstract":"Oral absorption of a drug is modeled by the differential equations for dissolution, permeation and gastrointestinal transit processes. The purpose of the present study was to compare simple approximate analytical solutions with full numerical solutions for the calculation of the fraction of a dose absorbed (Fa). The GI compartment model for numerical integration consisted of 1 stomach, 7 intestine and 1 colon compartments, whereas for analytical solutions a simple one well-stirred compartment was used. Full numerical solutions were obtained by numerically integrating the dissolution, permeation and gastrointestinal transit differential equations. In the numerical integration calculation, the concentration change in the GI tract, particle size reduction, transit of drugs, etc., was dynamically simulated. Precipitation in the GI tract and regional differences of solubility and permeability were not considered. In total, 7056 numerical integrations were performed, sweeping practical drug parameter ranges of solubility (0.001 to 1 mg/mL), diffusion coefficient (0.1 – 10 x 10 -6 cm 2 /sec), dose (1 to 1000 mg), particle diameter (1 to 300 μm) and effective permeability (0.03 – 10 x 10 -4 cm/sec). The analytical solutions investigated were (I) a sequential first order approximation (Fa =1–Pn/(Pn – Dn)exp(–Dn) + Dn/(Pn – Dn)exp(–Pn), Dn: dissolution number, Do: dose number and Pn: permeation number. Dn, Do and Pn are the dimensionless parameters which represent the dissolution time/GI transit time ratio, the solubility/dose ratio, and the permeation time/GI transit time ratio, respectively), (II) a limiting step approximation (the minimum value of Fa = 1–exp(–Pn), Fa = Pn/Do and Fa = 1–exp(–Dn)) and (III) a steady state approximation for the dissolved drug concentration (Fa =1–exp(–1/(1/Dn + Do/Pn)), if Do < 1, Do = 1). Fa values by (I) and (II) were higher than those by numerical integration for low solubility compounds (r 2 = 0.80 and 0.98, root mean square error (RMSE) = 0.28 and 0.079, respectively). By applying the steady state approximation, the correlation was improved (r 2 = 0.99, RMSE = 0.047). The steady state approximation for the dissolved drug concentration was appropriate for Fa calculation.","PeriodicalId":40659,"journal":{"name":"Chem-Bio Informatics Journal","volume":null,"pages":null},"PeriodicalIF":0.3,"publicationDate":"2009-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78834088","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 geometry-dependent atomic charge calculation with modified charge equilibration method","authors":"K. Aoki, S. Tanaka, T. Nakano","doi":"10.1273/CBIJ.9.30","DOIUrl":"https://doi.org/10.1273/CBIJ.9.30","url":null,"abstract":"We have improved a modified charge equilibration (MQEq) method for calculating the geometry-dependent distribution of atomic charges. In this paper, Ohno-Klopman, Ohno and DasGupta-Huzinaga equations are adopted to express the shielding effect, and the calculated atomic charges with these MQEq methods are in good agreement with those by the HF/6-31G(d,p) calculations for several organic molecules. These MQEq methods would be useful to estimate the charge distribution for large molecules.","PeriodicalId":40659,"journal":{"name":"Chem-Bio Informatics Journal","volume":null,"pages":null},"PeriodicalIF":0.3,"publicationDate":"2009-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74707116","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":"Validation of ArgusLab Efficiencies for Binding Free Energy Calculations","authors":"A. Oda, O. Takahashi","doi":"10.1273/CBIJ.9.52","DOIUrl":"https://doi.org/10.1273/CBIJ.9.52","url":null,"abstract":"We conducted a docking efficiency validation of ArgusLab, a free docking software program. In this study, the calculated binding free energies of protein-ligand complexes by scoring functions were compared with experimental binding affinities. Correlations between the calculated and experimental data were evaluated for 11 ArgusLab settings and compared. Our results indicate that ArgusLab is useful for virtual screening and the weight of van der Waals interactions are unimportant for binding free energy calculations using this software.","PeriodicalId":40659,"journal":{"name":"Chem-Bio Informatics Journal","volume":null,"pages":null},"PeriodicalIF":0.3,"publicationDate":"2009-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1273/CBIJ.9.52","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72542530","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":"Prediction of fragile points of coiled coils","authors":"Hideki Tanizawa, M. Taniguchi, Ganga D. Ghimire, S. Mitaku","doi":"10.1273/CBIJ.9.12","DOIUrl":"https://doi.org/10.1273/CBIJ.9.12","url":null,"abstract":"A prediction system for identifying the region of flexible regions of the coiled coil was developed to determine the bending positions of the myosin rods using atomic force microscopy (AFM) and to analyze the molecular structures of proteins containing coiled coils. The prediction system comprises two modules: identification of heptad break points and prediction of fragile points in the coiled coil due to the hydrophilic core or hydrophobic outfield region. Here, we investigated the myosin rods using this prediction system. The results of AFM imaging showed four main flexible regions in a single myosin rod and of the 17 possible fragile points predicted, 16 were located in the four experimental bending regions. Next, we examined the enhanced fluctuation around these predicted fragile points using the B-factor for the three dimensional structure of coiled coil proteins from the SCOP database and found that the fluctuations in the hydrophilic core regions were significantly larger than those in the regions of the normal coiled coil. In contrast, the fluctuations in the hydrophobic outfield regions were reduced, suggesting a structural change of the coiled coils to balance these regions. Thus, the dynamic changes in the structure of the coiled coils around the fragile points may be related to the biological functions of the proteins. The prediction tool which developed in this work was incorporated in the SOSUIcoil system which predicts the coiled coil regions.","PeriodicalId":40659,"journal":{"name":"Chem-Bio Informatics Journal","volume":null,"pages":null},"PeriodicalIF":0.3,"publicationDate":"2009-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74476388","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":"Pharmacokinetic strategy for designing orally effective prodrugs overcoming biological membrane barriers: proposal of kinetic classification and criteria for membrane-permeable prodrug-likeness","authors":"T. Mizuma","doi":"10.1273/CBIJ.8.25","DOIUrl":"https://doi.org/10.1273/CBIJ.8.25","url":null,"abstract":"Chemical modification of an active drug with promoiety to a prodrug (“prodrugging”) is a way to improve the pharmacokinetic characteristics of an active drug in the body; however, no kinetic principles have been proposed to design orally effective prodrugs to overcome biological membrane barriers. Therefore, based on a previously reported kinetic model of drug absorption [Mizuma et al., J Pharm. Sci. 85, 854 (1996)], conditional equations for the kinetic strategy of prodrugging were derived. Conditional equations contain terms of uptake (influx) and efflux transport of the prodrug and drug, and the metabolism of the prodrug to drug. Thereby, kinetic classification and criteria for effective membrane-permeable prodrugs are shown as a decision tree with conditional equations. The first point in the kinetic classification and criteria is the uptake process; second, the efflux process is vetted; finally, the metabolic process is elucidated. In some cases, metabolism is not a factor in the better absorption of prodrugs than active drugs. Experiments corresponding to particular processes were proposed, and are applicable to the design of prodrugs not only for intestinal absorption, but also for biological membrane permeation.","PeriodicalId":40659,"journal":{"name":"Chem-Bio Informatics Journal","volume":null,"pages":null},"PeriodicalIF":0.3,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89135154","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":"Classification and characterization of human full-length cDNA clones that are difficult to sequence","authors":"Akihiko Kishimoto, Yukio Ono, K. Murakawa, T. Ishibashi, A. Wakamatsu, K. Kanehori, N. Nomura, T. Isogai, M. Yohda, S. Sugano","doi":"10.1273/CBIJ.8.1","DOIUrl":"https://doi.org/10.1273/CBIJ.8.1","url":null,"abstract":"In the Full-length Human cDNA Sequencing Project, 30,160 cDNA were sequenced. Among them, our group performed sequencing of 3,588 cDNAs, mainly using the primer walking method. The sequences achieved an average Phrap score of 76, which means the average of expected sequence accuracy was 99.9999975%, by sequencing of both strands with the criterion of a Phrap score over 30. In spite of the extremely high sequence reliability, we met with difficulty in sequencing 52 cDNAs, which are termed undecipherable cDNAs. cDNAs of long repeats were considered as a possible source of sequencing difficulty; their maximum repeat length sequenced by the primer walking method was 530 bp, without using the random method, and 81% of long repeat sequences remained in the ORFs. In single repeat regions, the insertion/deletion rates were much larger than in the usual regions. The fraction of SINE/Alu repeats in the cDNAs was 5.4%, half of the fraction of the human genome. The fraction of SINE/Alu in undecipherable cDNAs was up to 10%, the same level of the human genome.","PeriodicalId":40659,"journal":{"name":"Chem-Bio Informatics Journal","volume":null,"pages":null},"PeriodicalIF":0.3,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85575991","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":"A high performance prediction system of coiled coil domains containing heptad breaks: SOSUIcoil","authors":"Hideki Tanizawa, Ganga D. Ghimire, S. Mitaku","doi":"10.1273/CBIJ.8.96","DOIUrl":"https://doi.org/10.1273/CBIJ.8.96","url":null,"abstract":"The coiled coil structure in proteins is characterized by heptad repeats of hydrophobic amino acids, but many breaks of the heptad repeats are observed within coiled coil regions which are the main cause of the errors in the currently used prediction systems for coiled coils. For understanding the characteristics of coiled coils including heptad breaks, the features of coiled coils were studies focusing on three problems: (1) the determination of appropriate register for the breaks in heptad repeat regions, (2) the discriminations of coiled coil regions using physical properties of amino acid segments which have heptad repeats and (3) the elucidation of the structural difference among several types of heptad breaks. Appropriate registers of heptad repeats and breaks were determined by two steps: first, the typical template of heptad repeats was applied to amino acid sequences and then several types of template for heptad breaks were applied to the segments around inconsistent points of the heptad repeat regions, leading to the most appropriate registers. Then, the coiled coil regions were discriminated from other types of regions by the canonical discriminant analysis, using ten parameters (three physicochemical properties and seven number densities of amino acids). The novel coiled coil prediction system SOSUIcoil showed better performances of coiled coil prediction than other prediction systems. Furthermore, the structures of segments around the heptad breaks were analyzed, indicating that some types of heptad breaks tend to form coiled coil structure whereas the other types are at the end of coiled coils.","PeriodicalId":40659,"journal":{"name":"Chem-Bio Informatics Journal","volume":null,"pages":null},"PeriodicalIF":0.3,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80866636","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}