Benchmarking Affinity-Based Docking for Irreversible Acetylcholinesterase Inhibitors: A Physics-Informed Reactivity Framework for Stereoselective Potency Prioritization

We benchmark that assumption against a curated set of measured human-AChE inhibition rate constants (<i>n</i> = 14; G-, V-, and organophosphate-pesticide classes, including a configuration-resolved VX pair).

AutoDock Vina affinity (Spearman ρ = +0.12) and GNINA CNN scores (ρ = −0.40) do not provide statistically reliable potency rankings; explicit covalent docking also remains weak (ρ = +0.23, <i>n</i> = 11), with bootstrap confidence intervals crossing zero. Selecting covalent-compatible (near-attack) poses rather than top-ranked poses does not change this outcome. A quantum-chemical cluster scan supports a mechanistic interpretation: once the activated serine alkoxide/reactive complex is formed, P–O bond formation is downhill within the model, so the discriminating information is expected to reside in electrophilicity, leaving-group chemistry, and transport into reactive geometry rather than in a single docked pose.