The Yale Center for Molecular Discovery (YCMD) provides biology and chemistry services to the research community. Our staff has extensive experiences in academia, biotechnology, and the pharmaceutical industry with expertise in target validation, assay optimization, screen prosecution, drug discovery, and development. The newly renovated Center at Yale’s West Campus consists of approximately 10,000 sq. ft. of research laboratory space on the first floor of the Molecular Innovations Center building. Laboratory space includes over 30 benches, 10 medicinal chemistry hoods, seven cell culture hoods, and all of the instrumentation required to perform high throughput screening of compounds and siRNAs. The Center offers access to small molecule compound, natural product, and siRNA collections as well as expertise and instrumentation for high throughput assay development and execution of in vitro and cell-based assays with multiple detection readouts including high content screening (HCS). YCMD also offers a range of medicinal, computational and synthetic chemistry services from members with expertise in organic synthesis, molecular design and virtual screening. Our approach is service-oriented and results-driven.
Standard sample shipment requirements:
Samples to be shipped at room temperature, wet ice, or dry ice as appropriate.
Depending on how developed the assay is when brought into YCMD will dictate the time and effort devoted to this stage. A robust and reproducible Z-prime statistic using a positive control compound or siRNA versus a DMSO solvent or non-targeting siRNA negative control is the goal. Other parameters are optimized to ensure the assay is as sensitive as possible while reducing false negative and false positive results. Typically, homogenous biochemical assays are faster to optimize, while cell-based, especially cell-based HCS formats require more experiments to be conducted during validation.
Most non-radioactive assay formats such as absorbance, fluorescence (FI, FP, FRET, and HTRF), luminescence, etc. can be conducted at YCMD. The Center has a collection of ~ 150,000 compounds, including commercially-available as well as proprietary compounds arrayed in bar coded 384 well plates as 10 mM DMSO stocks. This includes an extensive collection of FDA and EU approved drugs ideal for indication discovery exploration. A small collection of natural product extracts are also available. HTS instrumentation includes liquid handling robots and automated bulk dispensers to pin tool compounds and add reagents into assay plates, along with high-throughput plate readers to measure the results. Data analysis, storage, and retrieval are handled through IDBS ActivityBase Suite of tools. Following a screen, the YCMD will cherry-pick hits for confirmation, artifact detection, and perhaps selectivity assays. Following hit validation, the YCMD chemistry group will work with investigators to determine which hits are potential candidates for chemistry optimization or cluster expansion via SAR by catalog. Price listed is for compound utilization only, project specific labor and reagents are additional and will be incorporated into the estimate.
The YCMD has the GE IN Cell analyzer 2200; a high-speed automated microscope-based, high-content imaging system useful for cell-based phenotypic assays. In contrast to traditional HTS, which typically has a single read out of activity, HCS allows a scientist to measure many properties or features of individual cells or organisms at once. Data analysis is carried out with GE proprietary software or readily available CellProfiler image analysis software before final analysis is done with IDBS ActivityBase Suite of tools. Project pricing would incorporate per plate charge for siRNA or small molecule, labor for cell culture activities, plate processing, imaging time, and data analysis.
The YCMD has the GE IN Cell analyzer 2200; a high-speed automated microscope-based, high-content imaging system useful for cell-based phenotypic assays. Capabilities include multiparameter, simultaneous 4 color detection via a solid state laser illumination system and appropriate filters with detection via 5.5 MPixel CMOS camera. This is paired with a paa KiNEDx robotic plate handling system for unattended operation. Options for only obtaining the image data files or complete analysis done at YCMD for an additional charge (see microscopy image analysis category).
HCS allows a scientist to measure many properties or features of individual cells or organisms at once. Data analysis is carried out with GE proprietary software or the free open-source CellProfiler image analysis software which both allow analysis at the well, cell, and organelle level. JMP and/or Pipeline Pilot can then be used for further metric analysis and data visualization. Final analysis to quantify viability as well as the relevant cellular features is done with IDBS ActivityBase Suite of tools. Pathway analysis can then be performed using MetaCore or other software to focus on genes of interest.
The Dharmacon human siGenome siRNA library at YCMD consists of 18,081 genes arrayed in 58, 384-well plates. The entire collection contains several subsets: 1) Druggable Genome library is arrayed in 9 plates and covers ion channels, proteases, phosphatases, kinases, ubiquitin conjugation proteins, and G-protein coupled receptors. 2) Drug Target library is arrayed in 15 plates and covers genes involved in apoptosis, senescence, nucleic acid binding, autophagy, DNA repair, characterized nuclear receptors, and other potential therapeutic targets. 3) Human Genome library is arrayed in 34 plates and includes genes not contained in other subsets including uncharacterized genes.
Four siRNA duplexes targeting different regions of a single gene are pooled into a single well. Transfection of siRNA pools into the desired cell type, treatment/activation depending on the system being studied, followed most often by Immunocytochemistry (ICC) staining and high content immunofluorescence imaging, although other plate based readouts are sometimes used. Price listed is for cost of the siRNA only, project specific labor and reagents are additional and will be incorporated into the estimate.
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