Just two decades ago we were only beginning to recognize the potential of automated technologies to enhance throughput in drug discovery research. Today, it is difficult to imagine a modern laboratory without robotic equipment.
“We see continuous trends toward increased reliability of robots, partially driven by the introduction of new types of motors,” reports Malcolm Crook, Ph.D., CTO, Process Analysis & Automation (PAA). “Another trend is toward smaller targeted systems, that still flexibly accommodate peripherals as needed.”
PAA will be presenting the “automate.it harmony,” its user interface for software integration, at the Society for Laboratory Automation and Screening (SLAS) meeting later this month.
Conventional small molecule discovery is driven by high-throughput screening (HTS) centers, complete with expensive robotics designed to move microplates between various stations for compound dispensing, assay dispensing, incubation, and optical screening.
The federally funded Molecular Libraries Program supports nine comprehensive screening centers, with the hub at the NIH Chemical Genomic Center—a large-scale ultra-high throughput operation capable of generating over 2 million datapoints per week. The NIH Center was set up to work on lesser known targets implicated in rare and neglected diseases.
“We routinely need to adapt our assays for targets with limited availability,” says Anton Simeonov, Ph.D., chief of the chemical genomics branch. “Working with a unique enzyme or primary cells from a patient with a rare disease calls for conservation of resources at each step.”
The center introduced multiple innovations in designing assays and in adapting them to their fully integrated GNF/Kalypsys robotic system. The system is capable of storing over 2.2 million compound samples, performing multiple assay steps in 1,536-well format, and measuring custom output signals. Three high-precision robotic arms circulate between peripheral units.
“Because we run dozens of protocols, each with its own sophisticated screening logic, our robotic engineers work closely with vendors to modify the source code in real time,” says Dr. Simeonov. The team fully redesigned the traditional dose-response screening protocol to conserve precious starting material. Instead of creating dilution series on the same plate, dilution series are created across plates, meaning that each plate had only one concentration of a given compound. This strategy helps to generate custom data curves and minimizes the potential errors stemming from liquid handling or equipment malfunction.
To further conserve the reagents, the center continuously develops companion assays of matching throughput. “The initial hits typically require confirmation by labor-intensive biophysical and biochemical counterscreens. We miniaturize secondary screens to run in a high-throughput format,” says Dr. Simeonov.
A screen for inhibitors of FEN1, a key DNA repair enzyme, combined a primary fluorogenic screen with a secondary chemiluminescent bead-based assay, both reliably deployed in 1,536-well format. The team continues to change the screening paradigm by adapting other technologies to HT format, including microscale thermophoresis and acoustic dispensing.