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ClickChem Quick Guide

What does ClickChem do?

ClickChem designs click-chemistry conjugates computationally. Paste SMILES for your payload and target, pick a preset, and the pipeline finds a compatible reaction, selects a linker, and generates the conjugated product with 2D/3D visualization.

Single-click vs Dual-click

Mode	Input	How it works
Single-click (ADC, PDC, Marker)	Mol1 SMILES + Target PDB (or two SMILES)	Detects reactive handles, installs handles if needed, picks a linker from the backbone library, executes one click reaction. Ideal for ADC design against a protein target.
Dual-click (Payload, Probe, Permanent)	Mol1 SMILES + Mol2 SMILES (both required)	Searches 2400+ bifunctional cross-linkers for one whose two ends match the handles on mol1 and mol2. Executes two sequential click reactions: mol1—linker—mol2. Reproduces ADC chemistries like Kadcyla (T-DM1).

Presets cheat sheet

Preset	Mode	Best for
ADC	Single	Antibody-drug conjugate design (cleavable linker, site planning)
PDC	Single	Peptide-drug conjugate (short cleavable linkers)
Marker	Single	Imaging/labelling probe (non-cleavable, short PEG)
Payload	Dual	ADC-style payload. Toggle Cleavability to pick non-cleavable (T-DM1) or cleavable (cathepsin/glucuronidase).
Probe	Dual	In-vivo probe: bioorthogonal (SPAAC/IEDDA preferred)
Permanent	Dual	Permanent bridge: non-cleavable, any length

Dual-click options

Option	Values	Meaning
Cleavability	Non-cleavable / Cleavable	Hard-filters linkers. Non-cleavable = stable bond (e.g. T-DM1 SMCC). Cleavable = cathepsin, glucuronidase, disulfide, hydrazone-sensitive.
Handle mode	Native / Engineered / SPAAC—IEDDA / IEDDA—SPAAC	Native: use the reactive handles already on your molecules (thiol, amine, etc.). Engineered: install a bioorthogonal handle per-molecule (advanced). SPAAC—IEDDA: mol1 gets azide (SPAAC), mol2 gets tetrazine (IEDDA) → heterobifunctional DBCO-TCO linker. IEDDA—SPAAC: reversed — mol1 tetrazine, mol2 azide.
Mol 1 / Mol 2 handle	SPAAC / IEDDA(Tz) / IEDDA(TCO)	Only shown when Handle mode = Engineered. Set independently per molecule. SPAAC (azide): pairs with DBCO/BCN on linker. IEDDA (tetrazine): pairs with TCO on linker. IEDDA (TCO): pairs with tetrazine on linker. Example: SPAAC + TCO → DBCO-PEG-Methyltetrazine linker.

Supported click reactions

Reaction	Handle pair
SPAAC	Azide + DBCO / BCN / strained alkyne
CuAAC	Azide + terminal alkyne
IEDDA	Tetrazine + TCO / norbornene / cyclopropene
Thiol-Maleimide	Thiol (Cys) + maleimide
Amide (NHS)	Primary amine (Lys) + NHS ester
Amide	Primary amine + carboxylic acid
Oxime	Aminooxy + aldehyde
Hydrazone	Hydrazine + aldehyde

Results bar legend

• MW — Molecular weight (Da). Linker + conjugate shown for dual-click.
• LogP — Partition coefficient (hydrophobicity). Lower = more polar.
• RotB — Rotatable bonds. Proxy for conformational flexibility.
• PEG — Number of –OCH₂CH₂O– repeat units in the linker.

3D viewer colours

• Blue — Payload (mol1)
• Green — Linker
• Red — Click bond
• Purple — Biomolecule (mol2)

Quick start: FDA-approved ADC demos

Click any of the 10 FDA-approved ADC buttons below the form to instantly load a pre-computed result. Each demo reproduces a real marketed drug conjugate (Adcetris, Kadcyla, Enhertu, etc.) and shows the pipeline's chemistry selection, linker choice, and conjugate structure.

Quick start: Kadcyla (T-DM1) manual

Select Payload (dual), leave Cleavability = Non-cleavable, Handle mode = Native.

Paste DM1 in Mol1:

COc1cc2cc(c1Cl)N(C)C(=O)C[C@H](OC(=O)[C@H](C)N(C)C(=O)CCS)[C@]1(C)O[C@@H]1[C@H](C)[C@@H]1C[C@@](O)(NC(=O)O1)[C@H](OC)/C=C/C=C(\C)C2

Paste a Lys surrogate in Mol2:

CC(=O)N[C@@H](CCCCN)C(=O)NC

Choose 3D (full) render and click Run Pipeline.

Quick start: Engineered SPAAC + IEDDA

Same DM1 + Lys above, but switch Handle mode to Engineered. Set Mol 1 to SPAAC (azide) and Mol 2 to IEDDA (TCO). The pipeline installs azide on DM1 (thiol) and TCO on Lys (amine), then searches heterobifunctional linkers like DBCO-PEGn-Methyltetrazine.