| 1. |
- Kauppi, Anna M., 1971-, et al.
(author)
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Inhibitors of type III secretion in Yersinia : design, synthesis and multivariate QSAR of 2-sulfonamino-benzanilides
- 2007
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In: Bioorganic & Medicinal Chemistry. - : Elsevier Ltd. - 0968-0896 .- 1464-3391. ; 15:22, s. 6994-7011
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Journal article (other academic/artistic)abstract
- Compound 1, 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-5-chloro-N-(3,4-dichloro-phenyl)-benzamide, was identified as a putative type III secretion inhibitor in Yersinia, and the compound thus has a potential to be used to prevent or treat bacterial infections. A set of seven analogues was synthesized and evaluated in a type III secretion dependent reporter-gene assay with viable bacterial to give basic SAR. A second set of 19 compounds was obtained by statistical molecular design in the building block and product space and subsequent synthesis. Evaluation in the reporter-gene assay showed that the compounds ranged from non-active to compounds more potent than 1. Based on the data multivariate QSAR models were established and the final Hi-PLS model showed good correlation between experimentally determined % inhibition and the calculated % inhibition of the reporter-gene signal.
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| 2. |
- Andersson, David C., 1978-, et al.
(author)
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A multivariate approach to investigate docking parameters' effects on docking performance
- 2007
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In: Journal of chemical information and modeling. - : American Chemical Society Publications. - 1549-9596 .- 1549-960X. ; 47:4, s. 1673-1687
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Journal article (peer-reviewed)abstract
- Increasingly powerful docking programs for analyzing and estimating the strength of protein-ligand interactions have been developed in recent decades, and they are now valuable tools in drug discovery. Software used to perform dockings relies on a number of parameters that affect various steps in the docking procedure. However, identifying the best choices of the settings for these parameters is often challenging. Therefore, the settings of the parameters are quite often left at their default values, even though scientists with long experience with a specific docking tool know that modifying certain parameters can improve the results. In the study presented here, we have used statistical experimental design and subsequent regression based on root-mean-square deviation values using partial least-square projections to latent structures (PLS) to scrutinize the effects of different parameters on the docking performance of two software packages: FRED and GOLD. Protein-ligand complexes with a high level of ligand diversity were selected from the PDBbind database for the study, using principal component analysis based on 1D and 2D descriptors, and space-filling design. The PLS models showed quantitative relationships between the docking parameters and the ability of the programs to reproduce the ligand crystallographic conformation. The PLS models also revealed which of the parameters and what parameter settings were important for the docking performance of the two programs. Furthermore, the variation in docking results obtained with specific parameter settings for different protein-ligand complexes in the diverse set examined indicates that there is great potential for optimizing the parameter settings for selected sets of proteins.
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| 3. |
- Andersson, Ida E., 1982-, et al.
(author)
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Probing Molecular Interactions within Class II MHC A(q)/Glycopeptide/T-Cell Receptor Complexes Associated with Collagen-Induced Arthritis.
- 2007
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 50:23, s. 5627-5643
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Journal article (peer-reviewed)abstract
- T cells obtained in a mouse model for rheumatoid arthritis are activated by a glycopeptide fragment from rat type II collagen (CII) bound to the class II major histocompatibility complex A(q) molecule. We report a comparative model of A(q) in complex with the glycopeptide CII260-267. This model was used in a structure-based design approach where the amide bond between Ala(261) and Gly(262) in the glycopeptide was selected for replacement with psi[COCH2], psi[CH2NH2+], and psi[(E)-CH=CH] isosteres. Ala-Gly isostere building blocks were then synthesized and introduced in CII260-267 and CII259-273 glycopeptides. The modified glycopeptides were evaluated for binding to the A(q) molecule, and the results were interpreted in view of the A(q)/glycopeptide model. Moreover, recognition by a panel of T-cell hybridomas revealed high sensitivity for the backbone modifications. These studies contribute to the understanding of the interactions in the ternary A(q)/glycopeptide/T-cell receptor complexes that activate T cells in autoimmune arthritis and suggest possibilities for new vaccination approaches.
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| 4. |
- Stenberg, Mia, 1979-, et al.
(author)
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A multivariate chemical map of industrial chemicals : Assessment of various protocols for identification of chemicals of potential concern
- 2009
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In: Chemosphere. - : Elsevier. - 0045-6535 .- 1879-1298. ; 76:7, s. 878-884
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Journal article (peer-reviewed)abstract
- In present study the Industrial chemical map was created, and investigated. Molecular descriptors were calculated for 56 072 organic substances from the European inventory of existing commercial chemical substances (EINECS). The resulting multivariate dataset was subjected to principal component analysis (PCA), giving five principal components, mainly reflecting size, hydrophobicity, flexibility, halogenation and electronical properties. It is these five PCs that form the basis of the map of organic, industrial chemicals, the Industrial chemical map. The similarities and diversity in chemical characteristics of the substances in relation to their persistence (P), bioaccumulation (B) and long-range transport potential were then examined, by superimposing five sets of entries obtained from other relevant databases onto the Industrial chemical map. These sets displayed very similar diversity patterns in the map, although with a spread in all five PC vectors. Substances listed by the United Nations Environment Program as persistent organic pollutants (UNEP POPs) were on the other hand clearly grouped with respect to each of the five PCs. Illustrating similarities and differences in chemical properties are one of the strengths of the multivariate data analysis method, and to be able to make predictions of, and investigate new chemicals. Further, the results demonstrate that non-testing methods as read-across, based on molecular similarities, can reduce the requirements to test industrial chemicals, provided that they are applied carefully, in combination with sound chemical knowledge.
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