Tatsuya Takagi
Osaka University
Japan
Title: In silico analysis of enantioselective binding of IMiDs to cereblon
Biography
Biography: Tatsuya Takagi
Abstract
Thalidomide and its analogs, lenalidomide and pomalidomide (referred to as immunomodulatory drugs or IMiDs) have been known to treat multiple myeloma and other hematologic malignancies as well as to cause teratogenicity. Recently the protein, named cereblon, was identified as the primary target of IMiDs, and crystallographic studies of the cereblon-IMiD complex showed strong enantioselective binding for the (S)-enantiomer of IMiDs. Here, 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. Our docking results provide novel insights into the binding mode of IMiDs-like molecules and contribute to a deeper understanding of cereblon-related biology.