Can ternary-complex scoring rank close PROTAC linker analogues? A matched-pose test
- Linker optimization in targeted protein degradation is still largely empirical.
- The preprint asks whether current computational methods can rank close linker analogues before synthesis, the finest chemical differences yet tested.
- It uses a matched-pose design on VHL-recruiting SHP2 degraders to isolate the effect of the linker.
- This is a preprint, not yet peer reviewed; the snippet-level abstract available limits detail on the outcome.
💡 Points
Linker tweaks are where PROTAC campaigns burn months of synthesis, so an honest test of whether scoring can separate near-identical analogues is more useful than another headline-grabbing benchmark. Matched poses remove the usual excuse that the method just got the geometry wrong. Even a negative answer helps: it tells us to keep building degradation and cooperativity assays rather than trusting a docked score.