Fragment-contribution analysis ranks hit growth vectors and retrospectively matches the routes taken on Notum inhibitors
- A decision-support algorithm combines structure-based design with reverse fragment-based design, scoring each fragment's contribution to binding energy and its group efficiency to recommend where to grow a hit.
- Applied retrospectively to a Notum carboxylesterase inhibitor series, its prioritized growth vectors correlated well with the optimization strategies actually pursued experimentally.
- The stated aim is to cut the variability of expert judgment and wasted effort at the hit-to-lead stage.
💡 Points Based on the abstract
Agreement with the published route on one series is weak evidence: those routes are the survivors, and Notum is a crystal-friendly, well-behaved target. I'd ask what it recommends for the vectors that were tried and failed, and whether per-fragment energy decomposition, which is noisy, can separate neighbouring vectors. Good as a prompt for the design meeting, not a substitute for it.