title: In silico analysis of enantioselective binding of immunomodulatory imide drugs to cereblon.
abstract: 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 β10-β11 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871 Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Murai
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871 Japan ; Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871 Japan.
authors.forename: Norihito
authors.initials: N
authors.lastname: Kawashita
authors.affiliation: Graduate School of Information Science and Technology, Osaka University, 1-5 Yamadaoka, Suita, Osaka 565-0871 Japan.
authors.forename: Yu-Shi
authors.initials: YS
authors.lastname: Tian
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871 Japan ; Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871 Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Takagi
keywords: Cereblon; Docking simulation; Enantiomeric selectivity; IMiDs; Teratogenicity