Expand a hit into a library, and measure every single member.

The usual tag is a barcode, read by sequencing

Encoded library screening is any approach in which each member of a compound library carries a tag that records its chemical identity, so the members can be pooled, screened together, and told apart afterwards.

In a DNA-encoded library (DEL) the tag is a DNA barcode read by next-generation sequencing after selection and washing. What comes back is an enrichment count: how much more often a barcode appeared in the bound fraction than in the input. The count is a ranking signal, not an affinity, and it describes the intended synthesis product rather than the molecule that actually bound.

Here the tag is an address, read by the instrument

The workflow on this page uses the DNA differently. It is not read as a message, it is used as an address. Each chemical core is coupled to its own capture sequence, and DNA-directed immobilization (DDI) places it at one defined position on the sensor chip.

The instrument then reports a binding curve for that position. Identity comes from where the signal appears, not from sequencing what was pulled down. The tag is never amplified, never sequenced, and never decoded.

Axis one, the core, lives in space

A library built by combining n cores with m building blocks has two independent axes. The concept assigns each axis to a different physical channel, so neither has to be decoded from the other.

Every core is coupled to its own DNA capture sequence, so DDI places it at one known position on the chip. Position is identity, and it is fixed before any measurement starts.

Axis two, the building block, lives in the sample

The addressed cores are pooled once, then split into aliquots, and each aliquot is reacted with a single building block. Every aliquot therefore contains all n cores carrying the same building block.

Which aliquot you inject is the second half of the identity. A compound is then specified completely by the pair (position, sample). No barcode has to be sequenced, and no deconvolution step stands between the measurement and the answer.

This is the whole mechanism, and it is deliberately simple. Everything else on this page follows from it.

DNA-directed immobilization places each core at a predefined position, which is what allows position to serve as identity. This sets the height of the matrix.

All positions on the chip are read in the same run under the same conditions, so values within one sample are directly comparable without cross-run normalization.

Each position returns an association rate, a dissociation rate, and an equilibrium dissociation constant K_D, so members separate on binding behaviour rather than on a single endpoint value.

The working range spans picomolar to micromolar affinities, so strong and weak members of the same library stay resolvable in one campaign without pre-sorting by potency.

Focal molography measures in unpurified media. That matters here because the injected sample is a reaction mixture rather than a purified compound.

Detection is label-free and comes from the diffraction of the mologram pattern itself, so nothing has to be attached to the compound in order to see it bind.

Every cell carries a measured number

The output is a filled matrix in which every cell is one compound and every cell carries a measured value. That is a different object from a ranked hit list, and it answers different questions.

The empty cells are data too

Because non-binders are measured rather than inferred from absence, the empty regions of the matrix are informative. A core that binds with one building block and a core that binds with forty are immediately distinguishable, which is a selectivity statement that enrichment counts cannot make.

Trends along a row show how one core responds to substitution. Trends down a column show which cores tolerate a given building block. Both readings come out of the same campaign at no extra cost, because the whole matrix was measured rather than sampled.

Every building-block reaction runs on DNA-coupled material in a pooled format and has to tolerate all cores at once. Reactions needing large reagent excess, or leaving poorly soluble products, are the limiting case.

Instrument time grows linearly with the number of samples, so the width of the set sets the campaign length. The throughput table above turns that into concrete numbers for three set sizes.

A campaign spanning many consecutive days places the stability requirement on the whole run series rather than on a single measurement. Long campaigns should be planned with that in mind.

Because identity is positional, the design has to separate a real binding difference from a position artifact. Placing replicate cores at different positions across chips is the direct control.

The workflow reports binding, not conversion. A cell showing no binding could be a true non-binder or a failed coupling, so orthogonal quality control on the diversification step stays necessary.

A matrix-shaped campaign needs a machine-readable result per position and per run rather than a per-chip summary, so the analysis pipeline should be agreed before the first sample is made.

On-DNA hit validation characterizes DEL hits in parallel on one sensor chip, directly from the selection eluate. Its output is exactly the set of confirmed cores this workflow consumes. DEL Hit Validation

Confirmed binders that are not inhibitors still have a use. Targeted protein degradation turns binding into function through ternary complex formation. Targeted Protein Degradation

The Fc receptor panel applies the same multi-position principle to a fixed, validated ligand set rather than to a combinatorial library. Fc Receptor Panel