Monomer binding modes of small molecules that modulate the kinetics of hIAPP amyloid formation.

ABSTRACT: Human islet amyloid polypeptide (hIAPP) forms amyloid fibrils that accumulate in pancreatic β-cells of Type II Diabetes (T2D) patients. Recently discovered small molecules that modulate the kinetics of hIAPP amyloid formation could serve as starting points for developing T2D therapeutics, but no structural or mechanistic rationale exists to explain their binding mechanisms or effects on hIAPP aggregation pathways. Here, we utilize all-atom molecular dynamics computer simulations to elucidate the binding mechanisms of an hIAPP aggregation inhibitor (YX-I-1) and an aggregation accelerator (YX-A-1) to disordered monomers of wild-type hIAPP and the naturally occurring pathogenic S20G hIAPP variant associated with early-onset T2D. We observe that the inhibitor exhibits substantially higher affi

SUBMITTER: Garcia M 

PROVIDER: S-EPMC12485789 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature