Allosteric inhibition of the PCSK9–LDLR interaction: structural insights for small molecule design

contact is modestly reinforced upon ligand binding. MI-based dynamic mapping shows that potent inhibitors preserve long-range coupling between the allosteric pocket and the LDLR-binding segment D374-C378, whereas weak inhibitors fail to maintain this communication pathway, similar to the inhibitor-free form. Together, these results define a structural dynamic axis that links localized interfacial modulation to long-range allosteric communication and provide a mechanistic framework for the design of next-generation allosteric PCSK9 inhibitors with enhanced potency and efficacy.