Molecular Glues Stabilize Water-Mediated Hydrogen Bonds in Ternary Complexes.

ABSTRACT: By stabilizing weak and transient protein-protein interactions (PPIs), molecular glues address the challenge of targeting proteins previously considered undruggable. Rapamycin and WDB002 are molecular glues that bind to FK506-binding protein (FKBP12) and target the FKBP12-rapamycin-associated protein (FRAP) and the centrosomal protein 250 (CEP250), respectively. Herein, molecular dynamics simulations were used to gain insights into the effects of molecular glues on protein conformation and PPIs. The molecular glues modulated protein flexibility, leading to less flexibility in some regions, and changed the pattern and stability of water-mediated hydrogen bonds between the proteins. In the FKBP12-FRAP-rapamycin complex, two out of three water-mediated hydrogen bonds present in the crystallog

SUBMITTER: Mathur A 

PROVIDER: S-EPMC12833552 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature