Structure-based Inhibitor Design for the Intrinsically Disordered Protein c-Myc

Sci Rep. 2016 Mar 2;6:22298. doi: 10.1038/srep22298.


Intrinsically disordered proteins (IDPs) are associated with various diseases and have been proposed as promising drug targets. However, conventional structure-based approaches cannot be applied directly to IDPs, due to their lack of ordered structures. Here, we describe a novel computational approach to virtually screen for compounds that can simultaneously bind to different IDP conformations. The test system used c-Myc, an oncoprotein containing a disordered basic helix-loop-helix-leucine zipper (bHLH-LZ) domain that adopts a helical conformation upon binding to Myc-associated factor X (Max). For the virtual screen, we used three binding pockets in representative conformations of c-Myc370-409, which is part of the disordered bHLH-LZ domain. Seven compounds were found to directly bind c-Myc370-409 in vitro, and four inhibited the growth of the c-Myc-overexpressing cells by affecting cell cycle progression. Our approach of IDP conformation sampling, binding site identification, and virtual screening for compounds that can bind to multiple conformations provides a useful strategy for structure-based drug discovery targeting IDPs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / chemistry
  • Cell-Free System
  • Drug Design*
  • Drug Evaluation, Preclinical
  • HL-60 Cells
  • Humans
  • Intrinsically Disordered Proteins / antagonists & inhibitors*
  • Intrinsically Disordered Proteins / chemistry*
  • Magnetic Resonance Spectroscopy
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Domains
  • Proto-Oncogene Proteins c-myc / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-myc / chemistry*
  • Structure-Activity Relationship
  • User-Computer Interface


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Intrinsically Disordered Proteins
  • Proto-Oncogene Proteins c-myc