Interactions between small molecules and an intrinsically disordered protein: small molecule inhibitors of the oncogenic transcription factor c‐Myc

Six, structurally unrelated, small molecule inhibitors of the complex formation between the bHLHzip domain of c‐Myc and its bHLHzip partner Max were found to function by binding to two, independent binding sites located on the c‐Myc bHLHzip. These sites are defined by local sequence segments of adjacent amino acids. This domain is intrinsically disordered when in complex with Max. The location of the two binding sites however correlates with the border regions between segments of predicted local structure and disordered segment. These results improve the understanding of the interaction mechanism between small molecules and intrinsically disordered proteins. They furthermore suggest the possibility of defining descriptors of such interactions on the basis of primary structure information.