Applications Drug Discovery 2016-11-21T17:53:15+00:00

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Drug Discovery Automation

Currently, the process of researching and developing a safe and effective drug is slow and expensive and has a high failure rate.  This process is estimated to take an average of 12 years and to have a risk adjusted cost of $500 million per drug.  This long and costly process is due largely to the inability of science to predict which of a virtually infinite number of possible small molecule drugs will prove to be safe and effective.  The following is a more detailed description of the drug research and development process, which includes:

• Target discovery, including target identification and validation

• Drug discovery, including lead generation, lead optimization, and process research and development

• Pre-clinical development, which involves testing a potential drug candidate for safety and efficacy in animals

• Clinical development, which involves testing a drug candidate for safety and efficacy in humans

 

Automated High Throughput Screening – HTS

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Automated High Throughput Screening – HTS (finding a needle in a haystack)

High-Throughput Screening or HTS allows a researcher to quickly carry out millions of biochemical, genetic or pharmacological tests. With the millions of data points generated by these screens, only a small percentage of active compounds, antibodies or genes that modulate a particular biomolecular pathway are usually found.

With high speed liquid handlers, small volumes and densely packed sample formats automated HTS has greatly reduced the amount of time it takes researchers to run a screen against a library of candidate compounds.

High Throughput Screening (HTS) is now optimized using the Lynx Liquid Handling Robot configured with a 96 Channel VVP Head. With the ability of independently controlling each tip with individual volumes and volume verification, an entire 96 well compound sample plate may be diluted and mixed in a single step. By using a worklist protocol method, it is now possible to take a compound plate that has an electronic file containing each wells compound, volume and concentration and calculate a corresponding amount of DMSO to dilute all the compounds to a standard concentration.

The liquid handling robot’s 96 VVP Head can be used to dilute compound plates for a HTS assay in multiple high throughput ways:

An entire 96 well compound plate can be diluted with different volumes in one aspirate and dispense step.
A 384 well compound plate may be diluted in 5 steps with a single aspiration and 4 dispenses since the head may multi-pipet different volumes over multiple plates (if total volume is less than 1000uL for multidispensing).
A serial diluted plate may be created by picking up either single rows of columns of tips to run the serial dilution over a single plate.
In addition, the single channel i8 independent VVP tips may also perform any of the above tasks with the same performance and validation and is required for applications like hit picking for a secondary screen when individual well and / or tube access is required.

High-throughput screening is key in the industrialized drug discovery paradigm. Today, many pharmaceutical companies are screening 100,000–300,000 or more compounds per screen to produce approximately 100–300 hits. On average, one or two of these become lead compound series. Larger screens of up to 1,000,000 compounds in several weeks may be required to generate something closer to five leads.

High-throughput screening is evolving not only as a discrete activity, but as a perspective that is expanding backward toward target identification and validation and forward to converting assay hits to qualified leads via information generated either within screens or through downstream, high-throughput ADME (absorption, distribution, metabolism, and excretion) and toxicity testing.

In terms of definition, high-throughput screening can be considered the process in which batches of compounds are tested for binding activity or biological activity against target molecules. Test compounds act as inhibitors of target enzymes, as competitors for binding of a natural ligand to its receptor, as agonists or antagonists for receptor-mediated intracellular processes, and so forth. High-throughput screening seeks to screen large numbers of compounds rapidly and in parallel. Yet in another sense, high-throughput screening is an evolving process that is today a discrete activity and may tomorrow become more highly integrated into a rapidly changing drug discovery paradigm.

Automated Compound Dissolution

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Automated Compound Dissolution with DMSO and a 96 Channel Head

Now high throughput compound dissolution is available with Dynamic Devices Lynx Liquid Handling Robot configured with 96 VVP Independent Volume Head. Just link plate dilution volumes with the Method Manager software data input manager and the 96 VVP Head aspirates 96 different volumes and transfers them according your spreadsheet to perfectly dilute every sample in a single step. With the 96 VVP Head there is now no need for multi-pipetting with an 8 channel arm or calibrating DMSO liquid classes over a wide range of volumes. Now, not only do actual dilution transfers take place 96 at a time, but the actual volumetric transfer information is recorded and the exact dilution is obtained and sent back to any LIMS.

That’s what the new 96 VVP Head offers, exact volumetric individual transfers using DMSO, Acetonitrile or water. All dilution liquids are validated on-the-fly taking into account temperature and viscosity so no liquid class calibration or multi-dispensing is necessary.

Automated Secondary Screening – Hit Picking

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High-Throughput Screening or HTS allows a researcher to quickly carry out millions of biochemical, genetic or pharmacological tests. With the millions of data points generated by these screens, only a small percentage of active compounds, antibodies or genes that modulate a particular biomolecular pathway are usually found.

Compounds resulting in ‘hits’ are collected for further testing in which, for example, the potency of an enzyme inhibitor or the binding affinity of a ligand for a receptor may be determined. After this second level of triage, ‘hits’ become lead compounds. Further synthesis may then be required to provide a variety of compounds structurally related to the lead.

These ‘hits’ then need to be removed form the massive compound libraries and condensed into another format for further analysis. In this process, 100’s of microplates have to be accessed in order to remove this small percentage of samples to a consolidation plate for the next series of tests. These sublibraries must then be screened against targets in order to choose optimal structures. At this stage, some basic indicators of toxicity or bioavailability may be considered in an attempt to eliminate potential failures as early in the discovery process as possible.

With the release of our LYNX Liquid Handling Robot Platform the ability to access individual tubes or microplate wells is realized. The new i8 Independent VVP Arm combines our Volume Verified Pipetting technology with independent channels to access any single position on the deck with monitored liquid transfers. The system is capable of transferring samples in DMSO or aqueous diluted samples without the development of liquid classes.

Dynamic Device T-Rx System Configuration

With an average hit rate of 1-10 samples per 96 or 384 well plates, many plates need to be brought to the liquid handler for just enough time to remove a few samples. This plate management capability of the T-Rx makes it possible to bring up to 9 plates to the system at once. The system uses a series of movable decks, Quick Decks, that it stores in vertical shelve units, and an elevator system load and unloads these decks on the liquid handler in under a minute. This fast pace plate movements gives the system just enough time to remover the 1-5% hits needed to be consolidated for secondary screening.

Automated Mother / Daughter Microplate Replication

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Automated 96 & 384 Well Microplate Replication
Mother / Daughter, plate-to-plate transfer, plate replication and plate stamping are all considered a terminology for duplicating samples in microplates. Plate replication standardizes the original format of the samples and gives the laboratory the ability to quickly and efficiently transfer samples, either 96 or 384 samples at a time, depending on if the systems heads a 96 or 384 head configuration, thus leading to the term ‘stamping’ of samples since they are all done in one single motion.

In High Throughput Screening (HTS) applications, hundreds, thousands and even millions of samples from compound libraries need to be transferred into a 96, 394 and 1536 microplate format and reproduced many time in order to screen the compounds in multiple assays and different dilutions.

This is a standard function of either size of the Oasis Series Liquid Handling Robot Platforms, as shown above, with the deck position locating any combination of source plates, destination plates and disposable tips. A wash station for tips may also be implemented to reduce the cost of disposables.

Automated ADME Solutions – Absorption, Distribution, Metabolism, and Excretion

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ADME (absorption, distribution, metabolism, and excretion) describes the disposition of a compound within an organism. The four criteria influence the drug levels and the metabolism of a drug in cellular tissues and influence the performance of the compound as a drug. Sometimes, the potential or real toxicity of the compound is taken into account (ADME-Tox or ADMET).

Dynamic Devices offers several different liquid handling robot system configurations to accomplish the ADME assays, with the configuration depending on throughput and the ability to combine multiple assays on the same platform.

Standard ADME Assays:

  • Aqueous solubility
  • Partition coefficient – log d
  • Protein binding/Blood partitioning
  • In vitro drug absorption
  • P-gp mediated drug-drug interaction
  • In vitro drug metabolism
  • In vivo PK/BBB
  • Bioanalytical support
  • Cyp-mediated drug-drug interaction
  • Cardiac toxicity – herg
  • Cytotoxicity
  • Phospholipidosis
  • Genetic toxicity