Cover Feature: Nonstandard Factor VIIa Binding Mode Reveals S1 Pocket Plasticity in Trypsin‐Like Proteases (ChemMedChem 3/2026)

Depicted on the cover is the discovery of a collapsed S1 pocket conformation in Factor VIIa induced by an oxazole based inhibitor. The magnified view shows how ligand binding remodels the active site and displaces the 215–217 loop, creating an inactive conformation. Supported by extensive molecular dynamics simulations, this work demonstrates that such collapsed states occur spontaneously in many serine proteases. These insights establish S1 pocket plasticity as a general mechanistic feature and open new avenues for inhibitor design. Stefan Güssregen, Herman Schreuder, Gerhard Hummer, and co-workers (DOI: 10.1002/cmdc.202500846). The background was created with BioRender.com.