Drug Discovery

Automated Liquid Handling in Drug Discovery: Separating Hits from Noise

In high-throughput screening, small dispensing errors can create false hits and false misses. This article covers the failure modes to watch for and how non-contact dispensing can tighten the data.

DISPENDIX Team

Mar 20, 2026

The hidden cost of noisy primary screens

In early screening, the goal is not perfection. It is triage. You want the primary screen to be reliable enough that you trust what moves into confirmation. If your dispense step adds variability, you pay for it later in secondary assays, follow-up chemistry, and analyst time.

Hit rates in many biochemical and cell-based screens sit around 0.1 to 1%. At that scale, even modest assay noise can inflate the hit list. A 0.5% false-positive rate sounds small until you realize it can double the number of wells you need to retest.

Where liquid handling artifacts come from

Most problems are not dramatic failures. They are small biases that repeat across plates.

Volume drift at low dispense volumes

Tip-based systems can struggle below the low microliter range, especially with viscous reagents like DMSO-rich solutions.

Carryover between wells

With potent compounds, trace transfer can be enough to generate apparent activity in nearby wells or across plates.

Evaporation during long dispenses

In 384- and 1536-well plates, certain wells can drift quickly if plates sit open under constant airflow.

Mixing differences

At low volume, incomplete mixing after compound addition can appear in downstream biological analysis.

What good looks like: metrics to track

It helps to agree on a small set of quantitative checks before you compare instruments or protocols. Common choices include Z-prime (Z'), plate CV, signal-to-background, and DMSO tolerance curves. If the readout is luminescence or fluorescence, monitor edge effects explicitly by plotting signal vs well position.

Tip-based robots are not always the wrong choice

Modern pipetting robots are strong at microliter work, serial dilutions, and assays that need active mixing. If your workflow stays above a few microliters and you can tolerate tip costs, they can be a good fit. Many groups use them for bulk reagent additions and then add a specialized dispenser for nanoliter compound transfer.

Why non-contact dispensing is common in HTS

Non-contact systems avoid several common failure modes at once. A tip-free
dispenser such as the DISPENDIX I.DOT HT ejects droplets directly from a source plate. That removes disposable tip costs and reduces the risk of tip-mediated carryover.

I.DOT_LT_BS_15

Download the I.DOT brochure to learn more

A simple way to compare dispensing quality in your lab

If you want a fast, instrument-agnostic comparison, run these two tests:

1. Fluorescein or dye CV plate: Dispense into a full plate, read fluorescence or absorbance, and map the distribution across wells.
2. Alternating high-low carryover plate: Alternate a high-concentration tracer with blanks and measure whether blanks pick up signal.

Key takeaways

• In screening, you pay for dispense noise in follow-up work, not just in the primary run.
• Track Z', CV, and position effects. They diagnose issues faster than looking at hit lists.
• Non-contact dispensing can be a clean way to cut carryover risk and compound waste when you work at nanoliter scale.

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Drug Discovery

Automated Liquid Handling in Drug Discovery: Separating Hits from Noise

The hidden cost of noisy primary screens