MSM states from high flux activation pathways were assigned a progress score ξ based on structural metrics in and range from the inactive crystal structure (2RH1) at ξ=0 to the active crystal structure (3P0G) at ξ=1. Top ranking compounds from a retrospective virtual screen of known β2AR ligands at each MSM state, and both crystal structures, were clustered according to their 3D shape and chemistry overlap. Four examples of chemotype clusters enriched by select MSM states along the activation pathways are shown, with the percentage of a chemotype represented in the total ligands enriched at a given ξ. (a) Example agonist chemotypes are catecholamine derivatives (1, 2 and 3) and ethanolamine (4) derivatives. b) Example antagonist chemotypes (5, 6, 7 and 8) share a 2-hydroxy propyl amino core and include a carbostyril substituted pyridazinone (5), benzhydryl-amine (6), and pyridone nitriles (7, 8). The complete distributions along ξ for all agonist and antagonist chemotype clusters are shown in . These results show that docking to intermediates identified by MSM Transition Path Theory analysis enriches more diverse chemotypes that could be missed by screens of only a few structures.