The Vanderbilt HTS Facility provides a variety of services to the research community. Consultations are available for assay design, optimization, development, and validation, as well as integrating automated HTS and data analysis.
The compound collection can be accessed independently of screening, and HTS compatible supplies for testing and validation are available. Training services are also provided to allow for walk-up use of state-of-the-art instruments. To contact HTS staff to discuss specific needs, please complete the Intake Form. Staff will evaluate requests and provide information describing the suggested resources required.
Train independent users Screen compounds Compound distribution
ASSAY DESIGN AND VALIDATION
Through the advanced, HTS-compatible instruments, the HTS facility supports a wide variety of detection modalities for assay measurements including: absorbance, fluorescence, time-resolved fluorescence, fluorescence polarization, fluorescence resonance energy transfer (FRET), time-resolved FRET, luminescence, bioluminescence resonance energy transfer (BRET) and scintillation proximity assays (SPA). Cell-based and cell-free assays in experimental systems that have been used in prior models have included but are not limited to; recombinant proteins, membrane fractions, cellular isolates, cell lysates, cell lines, and whole model organisms (e.g., zebrafish, C. elegans, and yeast).
The HTS facility is proficient at helping research investigators develop HTS-compatible assays, obtain preliminary data for grants and funding opportunities, and to screen for the identification and investigation of new compounds for basic research and pharmacological discovery. Discoveries include novel modulators of G-protein coupled receptors, ion channels, transporters, proteases, oxido-reductases, cellular adhesion proteins, lipases, growth factor receptors, proto-oncogenes, protein-protein interactions, DNA-protein interactions, and other molecular targets and pathways that are important in numerous diseases such as neurodegenerative diseases, cardiovascular diseases, malaria, bacterial and viral diseases/illnesses, diabetes, cancer, and HIV.
- GPCR Modulators
- Ion Channel Modulators
- Cardiovascular Zebrafish Models
- Diabetes Targets
- Anti-Malarial Targets
- Foodborne Illness Targets
- Coagulation Inhibitors
- Transcriptional Modulators
- COX Inhibitors
- Choline Transporters
- Obesity and Cachexia Regulation Target
- Colon Cancer Targets
- Pancreatic Cancer Targets
- Lung Cancer Targets
- Breast Cancer Targets
A project begins with completion of an Intake Form. Once received, a HTS staff will schedule a consultation to discuss the adaptation and implementation of the assay to the HTS facility. Typically, assays are validated manually by individual laboratories and evaluated to determine the level of automation and instrumentation needed for HTS services. Once the assay is validated with positive and negative controls and the robustness of the assay (Z-factor/Z’) is determined the assay is ready to be automated. During validation of the automation, manual steps are replaced systematically with instruments to ensure accuracy and precision/fidelity of the assay as observed in the manual process. For example, manual pipetting into a 384-well plate can be replaced with use of a Thermo Multidrop, which dispenses liquid into an entire plate evenly and accurately in seconds. Another example is the Velocity11 Bravo liquid handler, this device can aspirate liquid from an entire plate, wash it, and add a solution to a plate very precisely in a matter of minutes. After determining the sequence of events and instrumentation for the assay, a robotic sequence called a schedule is created to integrate these assay procedures into an automated fashion.
Software determines the amount of time each sample will take during individual movements of the robot and the composite time for all samples to be assayed. Testing of the schedule begins with running the schedules for individual instruments, followed by testing of all instruments without reagents, and finally, testing of all instruments with water. Next, an experiment is run using all instruments and robotics integrated by the schedule with experimental controls. After the biological procedure and the instrumentation are validated, the assay is ready for compound screening. The growing library available for screening includes over 160,000 compounds.
A large number of data can be generated by HTS and our specialized HTS informatics staff can assist with custom-made software to help assimilate, analyze and reduce data to appropriate specifications for hit picking, follow-up analyses, and hit validation.
The compound collection at the HTS facility is comprised of several commercial and private sources. Depending on the research investigator’s interest subsets or the entire collection can be requested for testing using an online compound distribution request which allows plate type, volume, and concentration to be tailored to the investigator’s needs. The HTS strives to continually enrich the library with novel scaffolds and actively encourages investigators to deposit compounds into the library for distribution and screening. Synthetic and natural product chemists are also encouraged to contact the facility about deposition opportunities.
|LIBRARY||# OF COMPOUNDS||COMPOSITION|
|Vanderbilt Discovery Collection||100,632||Selected from Life Chemicals collection for HTS. The compounds in this collection were chosen by Vanderbilt medicinal and computational chemists to provide lead-like motifs, minimum pan-assay interference, and maximum diversity.|
|VICB Collection||145,150||Drug-like, diverse set of small molecules from Chembridge and ChemDiv.|
|Molecular Libraries Small Molecule Repository (MLSMR)*||76,575||Recent acquisition for MLPCN screens; requires screening results deposition into Pubchem.|
|Spectrum Collection 2400||2,400||A wide range of biologically active and structurally diverse compounds. 50% drug components, 30% natural products, 20% other bioactive components.|
|NIH Clinical Collection I and II||727||Small molecules that have history of use in human clinical trials.|
|Cayman Lipid Library||847||Broad variety of bioactive lipids.|
|Fesik Fragment Library**||16,000||Diverse collection of fragment molecules from 8 vendors, rule of 3 compliant, and filtered against non-specific and interfering molecules.|
|Marnett Collection||212||NSAID derivatives that contain cyclooxygenase inhibitors, PPARgamma activators, and apoptosis inducers.|
|Ion Channel||6248||A collection from Life Chemicals targeted to ion channels compiled using 2D fingerprint similarity methodology.|
|Epigenetics Collection||57||A group of small molecule modulators with biological activity for use in epigenetic research.|
|Enzo Kinase Inhibitor Library||80||The Screen-Well™ Kinase Inhibitor Library contains 80 known kinase inhibitors of well-defined activity. Includes inhibitors of these important kinases: Insulin/IGF Receptors, PI 3-Kinase, CaM Kinase II, JAK, PKA, CDK, JNK, PKC, CKI II, MAPK, RAF, EGFR, MEK, SAPK, GSK, MLCK, Src-family, IKK, PDGFR, VEGFR, and many more.|
|NCI Focused Natural Product Collection||936||Pure compounds acquired by the NCI from Analytical and MerLion.|
|NCI Approved Oncology Drugs Set VI||248||Contains most current FDA-approved anticancer drugs. The current set (AOD VI) consists of 119 agents and is intended to enable cancer research, drug discovery, and combination drug studies.|
|NCI Diversity Set V||1593||During the generation of the diversity set, the pharmacophores for any candidate compound are compared to the set of all pharmacophores found in structures already accepted into the set. If the current structure has more than 5 new pharmacophores, it is added to the set. An additional objective with the NCI Diversity Set III was to create a diverse set of compounds that were amenable to forming structure-based hypotheses.|
|NCI Mechanistic Set III||813||Derived from the 37,836 open compounds that have been tested in the NCI human tumor 60 cell line screen. In contrast to the original diversity set of 1,990 compounds, which was chosen on the basis of structural diversity.|
|NCI Natural Product Set III||117||This set was created in response to numerous drug discovery research groups that expressed a desired to study a variety of scaffold structures having multiple functional groups.|
|FDA-Approved Drug Collection||1184||A collection of 978 FDA approved drugs supplied as pre-dissolved DMSO solutions; purchased from SelleckChem.|
|Kinase Inhibitor Library 2017||429||A unique collection of 429 kinase inhibitors for high-throughput screening and high content screening. Supplied as pre-dissloved DMSO solutions: purchased form SelleckChem.|
|Anti-Cancer Compound Library||422||A unique collection of 422 anti-cancer compounds under clinical trials. Supplied as pre-dissloved DMSO solutions: purchased form SelleckChem.|
* Requires data deposit into PubChem
** Requires approval from Dr. Fesik
*** Requires collaborative agreement with supplier
TRAINING AND WALK-UP INSTRUMENT USE
Most of the HTS instruments are available for walk-up use. Instruments can be reserved online for as little as 15 minutes at a time, and instruments can be accessed 24 hours a day, seven days a week. A short training for every HTS instrument and automation is required for use and for reserving instrument time. Training includes understanding the capabilities of the instrument, the limitations, instrument functions and safety, data capture, analysis, access, and storage, as well as HTS facility policies and procedures for instrument access and use. Training time will be charged to the investigator’s account and generally lasts between 30-60 minutes, depending on the equipment being used. Following training access to the HTS facility and instrument reservation and usage will be granted. Our instruments can be found here.
GRANT WRITING INFORMATION
The HTS staff can help research investigators with HTS related grant writing and funding opportunities. The HTS staff will be happy to provide budget quotes, facility descriptions, and letters of recommendation and support. All new users need to complete the Intake Form for assistance with grants. If you are a current user or have questions, please contact Paige Vinson via email or call (615) 322-0342 for further information.
USABLE GRANT TEXT
Please contact HTS Staff for grant content to meet your specific needs: HTS@vanderbilt.edu
Listed below are several resources with information for funding HTS projects.
- VICTR Grants
- Vanderbilt University Funding Programs
- PAR-17-438 (NCI, NIAID, NIDCD, NIDA, NIMH) Assay development and screening for discovery of chemical probes or therapeutic agents (R01)
- Innovation Grants to Nurture Initial Translational Efforts (IGNITE): Assay Development and Therapeutic Agent Identification
- PAR-16-374 Assay Development and Screening to Discover Therapeutic or Imaging Agents for Diseases of Interest to the NIDDK (R01)
- NCI Experimental Therapeutics Program (NExT)
- ADDC Partnerships listed through the Academic Drug Discovery Cons