ClickChem: Automated Conjugation Chemistry Planning for Antibody–Drug Conjugates

Antibody–drug conjugates (ADCs) require precise conjugation chemistry to covalently attach cytotoxic payloads to monoclonal antibodies while preserving antigen-binding function and pharmacokinetic stability. The selection of an appropriate conjugation strategyencompassing the reaction family, the conjugation site on the antibody, and the linker architecture—remains largely empirical, relying on iterative experimental screens that are costly and time-consuming. We present ClickChem, a computational pipeline that auto-mates conjugation chemistry selection for ADC design. The pipeline operates in six sequential stages: functional-group detection on the payload, multi-conformer solvent-accessible surface area (SASA) scoring of antibody conjugation sites, chemistry family planning across seven reaction families, linker selection from a curated library, in silico bond formation via SMIRKSbased reaction execution, and product validation through a six-layer quality-control protocol incorporating Maximum Common Substructure (MCS) analysis. A distinguishing feature of the site-scoring module is an ensemble-averaged SASA calculation that generates multiple antibody conformations through an Anisotropic Network Model (ANM) and aggregates solvent-exposure statistics across the ensemble, yielding a confidence metric that penalises residues whose accessibility fluctuates between conformations. We evaluate the pipeline on three fronts. First, we verify concordance with established clinical precedent by exercising the pipeline on the payloads and conjugation-site annotations of ten FDA-approved ADCsincluding Adcetris, Kadcyla, Enhertu, and Trodelvy—and show that the pipeline selects the conventionally employed reaction family in all ten cases (10/10 concordance). Second, we present two end-to-end case studies—MMAF and Doxorubicin conjugated to a full-length IgG surrogate (PDB: 1IGT) via heterobifunctional SPAAC–IEDDA dual-click chemistrydemonstrating handle installation, site-specific conjugation at three distinct residue types