The drug miltefosine is a prototypic lipid-like compound thought to modulate membrane environments and thereby indirectly prevent receptor-mediated signaling events. In addition to its primary therapeutic indications ...
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The drug miltefosine is a prototypic lipid-like compound thought to modulate membrane environments and thereby indirectly prevent receptor-mediated signaling events. In addition to its primary therapeutic indications in cancer and leishmaniasis, miltefosine has also been shown to block immunoglobulin E receptor-dependent mast cell activation. Miltefosine and other alkylphospholipids that are active in mast cell degranulation assays contain a positively charged nitrogen and a phosphate group that are important for activity. In addition to alkylphospholipids, ceramides are also known to act on membrane environments and inhibit mast cell activation. We have systematically searched a very large compound collection for other lipid-like inhibitors of mast cell activation. Analogs of an initially identified screening hit were synthesized and preliminary SAR information was collected, leading to the identification of sulfoxide and amine oxide containing lipid-like compounds as new inhibitors of mast cell activation. Sulfoxide and amine oxide derivatives were found to be only slightly less active than miltefosine. (C) 2011 Elsevier Masson SAS. All rights reserved.
Background: The genomic information which is transcribed into the primary RNA can be altered by RNA editing at the transcriptional or post-transcriptional level, which provides an effective way to create transcript di...
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Background: The genomic information which is transcribed into the primary RNA can be altered by RNA editing at the transcriptional or post-transcriptional level, which provides an effective way to create transcript diversity in an organism. Altering can occur through substitutional RNA editing or via the insertion or deletion of nucleotides relative to the original template. Taking advantage of recent high throughput sequencing technology combined with bioinformatics tools, several groups have recently studied the genome-wide substitutional RNA editing profiles in human. However, while insertional/deletional (indel) RNA editing is well known in several lower species, only very scarce evidence supports the existence of insertional editing events in higher organisms such as human, and no previous work has specifically focused on indel differences between RNA and their matching DNA in human. Here, we provide the first study to examine the possibility of genome-wide indel RNA-DNA differences in one human individual, NA12878, whose RNA and matching genome have been deeply sequenced. Results: We apply different computational tools that are capable of identifying indel differences between RNA reads and the matching reference genome and we initially find hundreds of such indel candidates. However, with careful further analysis and filtering, we conclude that all candidates are false-positives created by splice junctions, paralog sequences, diploid alleles, and known genomic indel variations. Conclusions: Overall, our study suggests that indel RNA editing events are unlikely to exist broadly in the human transcriptome and emphasizes the necessity of a robust computational filter pipeline to obtain high confidence RNA-DNA difference results when analyzing high throughput sequencing data as suggested in the recent genome-wide RNA editing studies.
The recent emphasis in combinatorial library design has shifted from the design of very large diverse libraries to the design of smaller more focused libraries. Typically the aim is to incorporate as much knowledge in...
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The recent emphasis in combinatorial library design has shifted from the design of very large diverse libraries to the design of smaller more focused libraries. Typically the aim is to incorporate as much knowledge into the design as possible. This knowledge may relate to the target protein itself or may be derived from known active and inactive compounds. Other factors should also be taken into account, such as the cost of the library and the physicochemical properties of the compounds that are contained within the library. Thus, library design is a multiobjective optimization problem. Most approaches to optimizing multiple objectives are based on aggregation methods whereby the objectives are assigned relative weights and are combined into a single fitness function. A more recent approach involves the use of a Multiobjective Genetic Algorithm in which the individual objectives are handled independently without the need to assign weights. The result is a family of solutions each of which represents a different compromise in the objectives. Thus, the library designer is able to make an informed choice on an appropriate compromise solution. less
A successful fragment-based lead discovery (FBLD) campaign largely depends on the content of the fragment collection being screened. To design a successful fragment collection, several factors must be considered, incl...
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A successful fragment-based lead discovery (FBLD) campaign largely depends on the content of the fragment collection being screened. To design a successful fragment collection, several factors must be considered, including collection size, property filters, hit follow-up considerations, and screening methods. In this chapter, we will discuss each factor and how it was applied to the design and assembly of one or more fragment collections in a major pharmaceutical company setting. We will also present examples and statistics of screening results from such collections and how subsequent collections can be improved. Lastly, we will provide a summary comparison of selected fragment collections from literature. less
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