How does a small molecule bind at a cryptic binding site?

• DOI: 10.1371/journal.pcbi.1009817
• Publication Date: 2022-03-03T18:53:26Z
• Authors: Yibing Shan; Venkatesh P. Mysore; Abba E. Leffler; Eric T. Kim; Shiori Sagawa; David E. Shaw
• Keywords: Docking (animal); Rational design

Protein-protein interactions (PPIs) are ubiquitous biomolecular processes that central to virtually all aspects of cellular function. Identifying small molecules modulate specific disease-related PPIs is a strategy with enormous promise for drug discovery. The design drugs disrupt challenging, however, because many potential drug-binding sites at PPI interfaces “cryptic”: When unoccupied by ligand, cryptic often flat and featureless, thus not readily recognizable in crystal structures, the geometric chemical characteristics typical small-molecule binding only emerging upon ligand binding. rational inhibit would benefit from better understanding how such bind interfaces. To this end, we have conducted unbiased, all-atom MD simulations four inhibitors (SP4206 three SP4206 analogs) interleukin 2 (IL2)—which performs its function forming receptor—without incorporating any prior structural information about ligands’ In multiple events, molecule settled into stable pose interface IL2, resulting protein–small-molecule site identical observed an existing structure IL2-SP4206 complex. Binding stabilized IL2 groove, which when was bound emerged transiently incompletely. Moreover, free energy perturbation (FEP) calculations successfully distinguished between native non-native IL2–small-molecule poses found simulations, suggesting combination FEP may provide effective tool identifying determining designed sites.