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Abstract
BackgroundThalidomide 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.ResultsUsing 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.ConclusionsOur docking results provide novel insights into the binding mode of IMiD-like molecules and contribute to a deeper understanding of cereblon-related biology.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-016-2761-9) contains supplementary material, which is available to authorized users.
Highlights
Thalidomide and its analogs, lenalidomide and pomalidomide have been known to treat multiple myeloma and other hematologic malignancies as well as to cause teratogenicity
Docking results for immunomodulatory imide drugs or IMiDs (IMiDs) The eleven crystal structures of cereblon were obtained from the Protein Data Bank (PDB) (Table 1), and these structures were docked with the (S)-enantiomers [(S)-thalidomide, (S)-lenalidomide, and (S)-pomalidomide] and the (R)enantiomers [(R)-thalidomide, (R)-lenalidomide, (R)pomalidomide] of IMiDs
In this study, using in silico docking simulations, we aimed to confirm the enantioselective binding of IMiDs to cereblon and to identify the region of cereblon that contributes to this selectivity
Summary
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. In the early 1960s, the drug was banned from the market because of its teratogenic potential (Mcbride 1961; Lenz et al 1962) Despite this notorious effect, intensive research has been carried out with thalidomide due to its efficacy of inhibiting tumor necrosis factor (TNF)-α secretion and treating multiple myeloma and other hematologic malignancies (Sheskin 1965; Singhal et al 1999). Intensive research has been carried out with thalidomide due to its efficacy of inhibiting tumor necrosis factor (TNF)-α secretion and treating multiple myeloma and other hematologic malignancies (Sheskin 1965; Singhal et al 1999) In this context, attempts to augment the effect of the drug resulted in the development of its analogs, lenalidomide and pomalidomide.
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