In silico analysis of enantioselective binding of immunomodulatory imide drugs to cereblon

Background: Thalidomide and its analogs, lenalidomide and pomalidomide (referred to as immunomodulatory imide drugs or IMiDs) have been known to treat multiple myeloma and other hematologic malignancies as well as to cause teratogenicity. Recently the protein cereblon was identified as the primary target of IMiDs, and crystallographic studies of the cereblon-IMiDs complex showed strong enantioselective binding for the (S)-enantiomer of IMiDs. Results: Using the structures of cereblon and IMiDs [both (S)-enantiomers and (R)-enantiomers] we performed docking simulations in order to replicate this enantiomeric selectivity and to identify the region(s) contributing to this selectivity. We confirmed the enantioselective binding of IMiDs to cereblon with high accuracy, and propose that the hairpin connecting the beta 10-beta 11 region of cereblon (residues 351-355) contributes to this selectivity and to the increased affinity with IMiDs. Conclusions: Our docking results provide novel insights into the binding mode of IMiD-like molecules and contribute to a deeper understanding of cereblon-related biology.