Click Conjugation

Click Conjugation — Quick Guide

What is this?

Click Conjugation is a Conjugation Designer: select a protein target, choose conjugation sites, pick a payload, and the pipeline designs a complete antibody-drug conjugate (ADC) with linker selection and 3D visualization.

Workflow steps

#	Step	What to do
1	Protein	Select a preset antibody (Human IgG1, Cetuximab, Nanobody) or upload your own PDB.
2	Site selection	Pick conjugation strategy: Interchain Cys (hinge disulfides, DAR~4), Surface Lys (random, DAR~3-4), or Engineered Cys (site-specific). The pipeline scores and ranks candidate residues.
3	Payload	Paste a payload SMILES or select from library (MMAE, DM1, DXd, SN-38, Doxorubicin, PBD dimer). Set the linker type (cleavable/non-cleavable).
4	Run	Click Design ADC. The pipeline detects handles, selects chemistry, matches a linker, executes conjugation, and validates the product.

Step

What to do

Protein

Select a preset antibody (Human IgG1, Cetuximab, Nanobody) or upload your own PDB.

Site selection

Pick conjugation strategy: Interchain Cys (hinge disulfides, DAR~4), Surface Lys (random, DAR~3-4), or Engineered Cys (site-specific). The pipeline scores and ranks candidate residues.

Payload

Paste a payload SMILES or select from library (MMAE, DM1, DXd, SN-38, Doxorubicin, PBD dimer). Set the linker type (cleavable/non-cleavable).

Run

Click Design ADC. The pipeline detects handles, selects chemistry, matches a linker, executes conjugation, and validates the product.

Site selection strategies

Strategy	Sites	DAR	Used by
Interchain Cys	Hinge disulfide cysteines	~4	Adcetris, Padcev, Enhertu, Tivdak
Surface Lys	Solvent-exposed lysines	~3-4	Kadcyla, Mylotarg, Besponsa
Engineered Cys	Site-specific mutation (e.g. S239C)	2	Next-gen ADCs (ThioMab)

Strategy

Sites

DAR

Used by

Interchain Cys

Hinge disulfide cysteines

Adcetris, Padcev, Enhertu, Tivdak

Surface Lys

Solvent-exposed lysines

~3-4

Kadcyla, Mylotarg, Besponsa

Engineered Cys

Site-specific mutation (e.g. S239C)

Next-gen ADCs (ThioMab)

Supported chemistries

Chemistry	Handle pair	Example ADCs
Thiol-Maleimide	Cys thiol + maleimide linker	Adcetris, Polivy, Padcev, Enhertu, Trodelvy, Tivdak
Amidation (NHS)	Lys amine + NHS ester linker	Kadcyla, Mylotarg, Besponsa
SPAAC	Azide + DBCO/BCN (engineered)	Next-gen site-specific
IEDDA	Tetrazine + TCO (engineered)	Pre-targeted therapy

Chemistry

Handle pair

Example ADCs

Thiol-Maleimide

Cys thiol + maleimide linker

Adcetris, Polivy, Padcev, Enhertu, Trodelvy, Tivdak

Amidation (NHS)

Lys amine + NHS ester linker

Kadcyla, Mylotarg, Besponsa

SPAAC

Azide + DBCO/BCN (engineered)

Next-gen site-specific

IEDDA

Tetrazine + TCO (engineered)

Pre-targeted therapy

Linker types

Type	Mechanism	Example
Cleavable	Cathepsin B (Val-Cit-PABC), acid-labile, disulfide	Adcetris (mc-VC-PABC)
Non-cleavable	Stable thioether bond	Kadcyla (SMCC)

Type

Mechanism

Example

Cleavable

Cathepsin B (Val-Cit-PABC), acid-labile, disulfide

Adcetris (mc-VC-PABC)

Non-cleavable

Stable thioether bond

Kadcyla (SMCC)

3D viewer

Blue — Payload

Green — Linker

Red — Click bond

Purple — Antibody / biomolecule

Orange — Conjugation site (on structure)

Tips

Start with Human IgG1 + Interchain Cys + MMAE for a classic ADC (reproduces Adcetris/Padcev).

Try Surface Lys + DM1 to reproduce Kadcyla chemistry.

Toggle Cleavable/Non-cleavable linker to see how linker selection changes.

Upload your own PDB to design conjugates on custom targets.

Protein

🧬

Human IgG1

IgG1 — 1HZH (b12 scaffold)

🧬

Cetuximab

IgG1 — EGFR

🔬

Nanobody

VHH — camelid

📂

Custom

Upload PDB

Scoring preset

Payload

Payload SMILES

Linker SMILES (optional — skip catalog)

If provided, this linker is used directly instead of searching the catalog.

No site selected — pick one in the Sites table below.

Chemistry

from the selected site + payload

Select a site in the Sites table, then "Generate options".

Expert: custom handle (override)

Custom target/residue handle SMILES Custom payload handle SMILES

Expert mode: unrecognised handle (e.g. benzene) → no chemistry proposed. If the combination conjugates, the chemistry is deduced; if not, nothing is proposed. Re-run "Generate options" after editing.

All chemistry modes (advanced)

Click chemistry

Payload ← linker → Antibody

Linker type

Fallback handle (optional)

e.g. azide-Ser: CC(=O)NC(COC(=O)CN=[N+]=[N-])C(=O)NC

DAR (payload copies = top-N sites)

Selecting a DAR picks the top-N scored sites. Or hand-pick sites in the table.

Load a protein to begin

⚗️

Select sites & conjugate
to see click chemistry

Run conjugation to see results.