Biomedical subjects

Dongyu Sun

Publications and source records attributed to Dongyu Sun.

4 recordsLinked to original sources

PubMed2006

Quality assessment and analysis of Biogen Idec compound library.

A subset of the compound repository for lead identification at Biogen Idec was characterized for its chemical stability over a 3-year period. Compounds were stored at 4 degrees C as 10 mM DMSO stocks, and a small subset of compounds was stored as lyophilized dry films. Compound integrity of 470 discrete compounds (Compound Set I) and 1917 combinatorial chemistry-derived compounds (Compound Set II) was evaluated by liquid chromatography/mass spectrometry from the time of acquisition into the library collection and after 3 years of storage. Loss of compound integrity over the 3 years of storage was observed across the 2 subsets tested. Of Compound Set I, 63% of samples retained > 80% purity, whereas 57% of samples from Compound Set II had purity greater than 60%. The stability of the lyophilized samples was superior to the samples stored as DMSO solution. Although storage at 4 degrees C as DMSO solution was adequate for the majority of compounds, the authors observed and quantified the level of degradation within the compound collection. Their study provides general insight into compound storage and selection of library subsets for future lead identification activities.

Chromatography, Liquid↗

PubMed2006

A kinase-focused compound collection: compilation and screening strategy.

Lead identification by high-throughput screening of large compound libraries has been supplemented with virtual screening and focused compound libraries. To complement existing approaches for lead identification at Biogen Idec, a kinase-focused compound collection was designed, developed and validated. Two strategies were adopted to populate the compound collection: a ligand shape-based virtual screening and a receptor-based approach (structural interaction fingerprint). Compounds selected with the two approaches were cherry-picked from an existing high-throughput screening compound library, ordered from suppliers and supplemented with specific medicinal compounds from internal programs. Promising hits and leads have been generated from the kinase-focused compound collection against multiple kinase targets. The principle of the collection design and screening strategy was validated and the use of the kinase-focused compound collection for lead identification has been added to existing strategies.

Combinatorial Chemistry Techniques↗

PubMed2005

Adopting a practical statistical approach for evaluating assay agreement in drug discovery.

The authors assess the equivalence of 2 assays and put forward a general approach for assay agreement analysis that can be applied during drug discovery. Data sets generated by different assays are routinely compared to each other during the process of drug discovery. For a given target, the assays used for high-throughput screening and structure-activity relationship studies will most likely differ in their assay reagents, assay conditions, and/or detection technology, which makes the interpretation of data between assays difficult, particularly as most assays are used to measure quantitative changes in compound potency against the target. To better quantify the relationship of data sets from different assays for the same target, the authors evaluated the agreement between results generated by 2 different assays that measure the activity of compounds against the same protein, ALK5. The authors show that the agreement between data sets can be quantified using correlation and Bland-Altman plots, and the precision of the assays can be used to define the expectations of agreement between 2 assays. They propose a scheme for addressing issues of assay data equivalence, which can be applied to address questions of how data sets compare during the lead identification and lead optimization processes in which assays are frequently added and changed.

Activin Receptors, Type I↗

PubMed2002

A pathway-specific cell based screening system to detect bacterial cell wall inhibitors.

A pathway-specific cell-based screen is described to detect compounds that inhibit the biosynthesis of the cell wall of bacteria. The basis for detection is the discovery that the beta-lactamase gene from Citrobacterfreundii, cloned into Escherichia coli, is induced when cells are exposed to known cell wall inhibitors, and not just beta-lactam-based antibiotics. In a wild type host, cell wall inhibitors such as moenomycin, vancomycin, and ramoplanin, which are excluded by the outer membrane, only induce at high concentrations. However, these compounds, as well as fosfomycin, cycloserine, and cefoxitin, induce at concentrations at or below the MIC of a host carrying the envA-mutation, which causes a defect in the outer membrane. As additional proof that induction of beta-lactamase is the direct result of cell wall inhibition, a host strain carrying a temperature-sensitive mutation in the murG gene, whose product converts the cell wall intermediate Lipid I, to Lipid II, also induced beta-lactamase at the restrictive temperature. A protocol is described for screening samples in high-throughput mode.

Anti-Bacterial Agents↗