High Throughput Screening (HTS)
Sygnature Discovery offers high throughput screening along with additional hit identification tools including virtual screening, knowledge-based design, and fragment screening. Employing a comprehensive strategy for hit identification, we use the most effective methods to accurately pinpoint hit series that have the highest potential for evolving into compounds with drug-like properties. High throughput screening (HTS) supports the rapid identification of new chemical beginnings by integrating medicinal chemistry, biology, informatics, and state-of-the-art automation technologies. The intricacy of this procedure means various external elements (beyond the primary assay biology) impact the effectiveness and results of a high throughput screening. These include the calibre of the library and the strategies for identifying hits.
Generating High Quality Starting Points
There are many components involved in generating high quality starting points for a drug discovery project. These include quality robust assays, reliable automation, secure data, and the quality of the libraries. At Sygnature Discovery, we meticulously factor in all these elements (both in the creation of our high throughput screening libraries and capabilities and throughout each project) to ensure optimal results for our customers.
Compound Libraries
Our high throughput screening compound libraries are crucial for high-quality drug discovery starting points. Among these, our computational chemists have developed the LeadFinder Diversity Library. Additionally, we offer customised high throughput screening by including the option to screen other commercial or client-provided libraries.
LeadFinder Diversity Library (150k)
The LeadFinder Diversity Library contains 150,000 Compounds – Perfect for HTS Follow-Up. Low Molecular Weight and lead-Like properties with strict Control on Similarity for Varied Options. Each Compound is vetted by Sygnature Discovery’s Senior Medicinal Chemists. We offer freshly sourced solids, with analogues and building blocks for most compounds.
- Extensive Collection
- Expertly Designed
- Diverse Structures
- Quality Assured
- Ready Resources
LeadFinder Prism library (48k)
The Prism library, designed by Sygnature Discovery and developed for the European Lead Factory, contains 37,000 compounds. An extra 11,000 were internally produced using similar principles, with further compounds actively synthesised and added to the library annually. Compounds are drug-like with high chirality and FSP3 and the library contains novel natural product inspired scaffolds. The Prism Library offers exclusive access to up to 50 hits per screen for enhanced intellectual property protection. We also ensure that Hit structures are excluded from subsequent screens for two years after the completion of each project.
Additional library sets
The Enamine Protein-Protein Interaction library (40k) has lead-like compounds incorporating specific protein recognition patterns. The Enamine Kinase Focused library (24k) is based on >100 hinge binding cores ((≥2 H-bonds possible with hinge).
If you wish to screen libraries in addition to these, we offer the option to screen customer or other commercial libraries.
High Throughput Screening Workflow
The HTS Workflow is tailored to each of our client’s requirements, focusing on developing robust assays with a flexible approach, especially in selecting hits to balance false positives and negatives. Each project is managed by dedicated scientists and project coordinators, and are always supported by a senior member of the HTS team member. The process begins with assay development or transfer. Our HTS group then conducts a robust, reliable assay validation screen (pilot). This pilot screen tests assay automation performance and gives an early hit rate estimate.
Primary Screen
The primary screen tests single concentration per compound from libraries. It includes in-house and external libraries, plus any customer-provided libraries. This is followed by first cheminformatic triage for hit confirmation and counter screen selection.
Hit Selection and Profiling
A second triage for final compound profiling with concentration response curves uses a
nuanced approach for diverse project requirements and varying hit rates. Collaboration with customers and Sygnature’s computational chemists ensures quality hit identification using computational chemistry triage, counter screens, and orthogonal assays.
Enhanced Compound Tracking and Storage
Sygnature Discovery is dedicated to excellence in compound tracking and storage, ensuring the highest standards for research. Our High-Throughput Screening (HTS) system leverages a fully integrated informatics platform for superior data fidelity and precise compound tracking. Utilising Titian Mosaic SampleBank software, linked with our HighRes® automated system, we streamline the ordering of assay plates. HTS libraries are stored in a custom-built facility with controlled low humidity and ambient temperature, ensuring compound integrity. HighRes® stackers organise HTS source plates for accessibility. We employ continuous feedback from the HighRes® system to Mosaic, supplemented by regular library QC, to maintain compound quality.
- Integrated Informatics
- Efficient Ordering
- Optimal Storage Conditions
- Continuous Quality Monitoring
Quality Control at Sygnature Discovery
To maintain the highest quality of compounds in our High-Throughput Screening (HTS) campaigns, we regularly perform quality control (QC) checks. Using Liquid Chromatography-Mass Spectrometry (LCMS), we meticulously analyse samples from our HTS library source plates. Compounds that advance to the final stage of the hit validation phase, specifically during potency assessments (EC/IC50 determinations), undergo additional QC processes. Our HTS group operates in close coordination with the Compound Management Department. This collaboration is enhanced by our automated Azenta Store, which facilitates the inclusion and management of external screening libraries.
Advanced Automation in Sygnature Discovery’s HTS System
Our high throughput screening system, developed by HighRes Biosolutions, is designed for versatility, accommodating both cell and biochemical assays. Central to our automation is the Echo acoustic dispensing technology, ensuring highly accurate compound delivery. The system operates with remarkable reliability, routinely functioning for 20-30 hours continuously, and is available 24/7. Enhanced with full remote accessibility and CCTV monitoring, the system allows for prompt error detection and recovery.
- High Flexibility Design
- Precision Dispensing
- Reliability and Extended Operation
- Remote Monitoring and Control
Dynamic Scheduling for Efficiency
Utilising Cellario for dynamic automation scheduling, our system ensures uniform treatment across assays, even for those challenging to schedule. Sygnature Discovery integrates cutting-edge automation to ensure efficiency and precision in our HTS processes.
Data Analysis Excellence in HTS
Sygnature Discovery prioritises advanced data analysis capabilities to ensure accuracy and efficiency in HTS processes. Our information technology system is specifically designed to manage and analyse large, complex datasets, a crucial capability for High-Throughput Screening (HTS). We leverage Genedata Screener for data processing. This robust tool ensures efficient data management and analysis. Barcoded plate files are uploaded to Genedata Screener. The integration of plate barcodes with sample ID and location data from Mosaic guarantees data fidelity. This system enables the rapid upload and thorough interrogation of screening data, facilitating detailed analysis by plate, batch, and screen.
- Efficient handling of complex data
- Genedata Screener utilisation
- Seamless data integration
- Efficient data analysis
Why Sygnature Discovery for high throughput screening?
Our HTS libraries and methodologies are developed to navigate all associated complexities to ensure the quality of the hits. Our experience spans a wide range of target classes, therapeutic areas, and assay technologies.