Automation in the Drug Discovery Process: Delivering Analytical Chemistry to Biologists and Beyond

Over the past decade, advances in genomic- and proteomic-based research techniques and instrumentation have resulted in major breakthroughs in the elucidation of the structure and function of disease targets, providing greater opportunities for the discovery and design of target-based drugs. Alongside this, the incorporation of modern analytical chemistry methods and tools has contributed to the development of novel compound and small fragment-based libraries, enabling the design and screening of suitable drug candidates. These advances, however, have resulted in an increase in scientific labor, throughput requirements, and ultimately financial burden in the pharmaceutical industry.

As a result of an increase in the number of targets available for analysis and the availability of compound libraries, traditional manual experimentation methods have become unfeasible. The drive to rationalize and perform large-scale assays in a cost-efficient and robust environment makes laboratory automation a fundamental requirement in both biomedical research and the drug discovery industry. By reducing the number of repetitive manual tasks, the potential for error is reduced and significant time savings can be realized, allowing the scientist to concentrate on research rather than repetition.

Pharmaceutical companies have therefore invested in a wide range of automated instruments to increase the throughput across all stages of the drug discovery process, from target-based research, combinatorial and analytical chemistry, primary and secondary screening, and final analysis and quality control.

Automated instrumentation can range from simple handheld semiautomated pipets that dispense multiple aliquots, to benchtop pipetting robots for automated plate setup and automated units that screen assay plates, providing computerized readings. Fully automated platforms are also employed, combining multiple instruments such as robotic arms to transfer plates and samples to liquid handlers, incubators, plate washers, and screening systems. Linked with multiple end-point reading platforms, such workstations enable high sample throughput and processing of large numbers of data points, reducing time and labor.

Automated liquid handling

Automated liquid handling instruments in the low volume range are used routinely for pipetting samples and reagents in a wide range of core research laboratories, including DNA sequencing, gene expression profiling, biochemical and cell-based assays, antibody-based assays and crystallography screen setup, as well as chemical compound synthesis, modification, analysis, and screening. The design and setup of plates from compound libraries requires easy-to-use automated instrumentation capable of plate formatting and reformatting, serial dilution, plate replication, and hit picking following the identification of potential lead compounds. Automated liquid handling not only increases throughput, but reduces manual error during repetitive tasks, eliminating the risks involved with the handling of large amounts of potentially dangerous material such as radioactive or infectious samples.

Assay miniaturization‒Making more with less

As a result of the increasing number of chemical compounds and molecular targets for high-throughput screening (HTS), there has been a recent trend toward the miniaturization of assays to enhance assay throughput and screen times, reducing the amount of precious sample required and saving costly reagents. The introduction of high-density assay plates‒i.e., 384-, 1536-, and even 3456-well plates‒has facilitated the ability to minimize assay volumes. The manual handling of nanoliter volumes required in miniaturized assays, however, significantly increases the potential for error, experimental discrepancies, and failure. Indeed, successful results for many assays such as crystal screen setup or PCR rely heavily on the accuracy of drop placement and the reproducibility of pipetting, requiring considerable skill and practice. Even small errors in the dispense accuracy of sample DNA or RNA can translate into huge differences after amplification. It is therefore essential to ensure highly accurate, reproducible, low-volume pipetting in the nanoliter range.

The incorporation of nanoliter liquid handlers such as the mosquito® from TTP Labtech (Melbourn, Hertfordshire, U.K.), with a volume range of 25 nL to 1.2 μL, has proven successful in many laboratories. With easy integration into work flows and other automated equipment, mosquito HTS has been successfully employed for the rapid transfer of samples (1 μL or less) to plates or for the setup of high-content biochemical and molecular biology assays. Problems of reformatting original assays as well as plate-to-plate transfer are easily overcome due to the ability to transfer nanoliter samples between all plate sizes in one simple protocol. With low-cost disposable tips, mosquito HTS is capable of reformatting between plate types without the risk of cross-contamination. The ability of mosquito HTS to accurately dispense and mix multiple low-volume aliquots of varying viscosities is of particular value in next-generation sequencing (NGS), which requires highly accurate and consistent enzyme additions to ensure controlled DNA fragmentation. Automation and miniaturization of complex processes such as NGS results in significant time and cost savings.

Manual effort is still required to maintain automated equipment

The ability to streamline the drug discovery work flow in an efficient manner is vital in today’s drug discovery industry, which continues to push for maximum output with minimal investment, labor, and reagent cost. Despite extensive automation, manual input is still required for a large number of routine laboratory tasks: from reagent preparation, setup, and monitoring of analytical instrumentation to sample and plate transfer between storage units to analytical or HTS equipment, as well as the movement of samples between laboratories. Users of analytical instruments such as HPLC or mass spectrometers need to be continually aware of solvent levels in both supply and waste vessels, since failure can result in damage to expensive equipment, leading to unwanted down time and cost. There is also the possible threat of leakage of potentially dangerous solvents if waste levels overflow.

Solvent level monitoring in supply and waste vessels, however, can often be overlooked because these vessels are generally housed on benches below or behind analytical equipment, making visual monitoring difficult. Furthermore, in a multiuser environment typical of a central analytical laboratory, it is often difficult to rely on setting instruments to estimate solvent usage, since it is dependent on users accurately setting the starting levels and resetting the system each time a bottle is replaced. TTP Labtech’s aequus provides a noncontact solution for reliable, automated solvent monitoring. With easy-to-fit sensors attached to waste and supply vessels, solvent levels can be visualized on an instrument-mounted touchscreen display. The sensors accurately measure the level of liquid in a wide variety of nonconductive vessels, accurately compensating for vessel material (including glass and plastic) and wall thickness with a resolution of better than 0.5 mm.

Beyond automated platforms‒The future of automating the drug discovery process

Figure 1 lab2lab pneumatic transport system.

With the escalating number of biological samples, small molecules, fragments, and RNAi libraries available today, placement and removal of samples from –20° or –80° C stores can be a complex and time-consuming process. Despite the availability of a wide range of automated storage modules and automated instrumentation, the transfer of samples from store for analysis still requires manual effort. Often highly trained scientists spend considerable time placing and removing samples from remote storage rooms and transporting them between dedicated laboratories or areas for assay setup and analysis. These samples may then be taken for further study by other scientific groups or back to store.

The ability to integrate sample and compound stores into a laboratory work flow with automated sample selection and transport would significantly reduce manual intervention and labor, allowing scientists to devote more time to research. More recently, a solution involving TTP’s pneumatic transport technology, lab2lab (Figure 1), was successfully employed to automatically transfer chemical intermediates and compounds from medicinal chemistry laboratories to a remote analytical laboratory.1 This proprietary technology, originally used to place sample vials in comPOUND® storage units (TTP Labtech) and to transport cherry-picked samples from store over short distances within the laboratory, has been successfully extended for the automated transport of newly synthesized chemical compounds in multifloor buildings. Current studies are also underway on long-distance transfer of many hundreds of meters between buildings. By employing lab2lab to transport samples between multifloor buildings, the throughput speeds of multiple analyzers was significantly enhanced, providing rapid feedback and thereby easing the work flow and increasing the rate of compound synthesis. lab2lab enables these medicinal chemists to obtain information on a larger range of intermediate samples, some of which may not have been previously analyzed, while pursuing multiple stages of synthesis and modification.

Although initially focused on the needs of the medicinal chemist, lab2lab has the potential to link scientific laboratories across a range of disciplines and processes. It can be applied to ease sample transport throughout the entire drug discovery process, connecting synthesis to purification, and biological screening and back to storage facilities.

This ability to automatically retrieve samples from a store and send them directly to analytical instrumentation or to a biological screening program across a research site is another step toward increased efficiency within the drug discovery pathway.

Discussion

In an era in which financial limitations are being constantly challenged, pharmaceutical companies need to consider the economic effects of the incorporation of new technologies into their work flow, while continuing to improve the productivity of drug discovery and development. The introduction of automated laboratory work flows across the disciplines in drug discovery has revolutionized throughput within this industry, and it is now possible to perform robotic ultrahigh-throughput screening of hundreds of thousands of chemical entities against a biological target within a short time frame.

The benefits of automation in the drug discovery process are numerous, increasing research quality, capacity, and throughput, to name a few. However, integration between automated workstations can prove complex, inflexible, and costly, and the general trend in the drug discovery industry is for manual sample transfer between individual workstations. The introduction of intelligent transport systems, such as lab2lab, enables automated transfer of samples between workstations, laboratories, and departments. Subsequently, the vision of fully accessible automation within and across drug discovery disciplines is close to being realized.

Laboratory automation on this scale has several benefits, permitting highly qualified scientists to concentrate their efforts on further understanding the disease mechanisms involved and the design of important novel approaches for the discovery of new therapeutics. The implementation of automated work flows also opens up the potential for better collaboration and communication between scientists, making drug discovery research a truly multidisciplinary process.

Reference

  1. Gaisford, W.; Everatt, B. Lab management and transport system. A tutorial. GEN Jun 2011, 31(12).

Wendy Gaisford, Ph.D., is the Science Writer at TTP Labtech, Melbourn Science Park, Melbourn, Hertfordshire SG8 6EE, U.K.; tel.: +44 1763 262626; fax: +44 1763 261964; e-mail: wendy.gaisford@ttplabtech.com.

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