title: Structure-based Inhibitor Design for the Intrinsically Disordered Protein c-Myc.
abstract: 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.
authors.affiliation: BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Yu
authors.affiliation: Beijing Nuclear Magnetic Resonance Center, Peking University, Beijing 100871, China.|College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Niu
authors.affiliation: Center for Quantitative Biology, Peking University, Beijing 100871, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Jin
authors.affiliation: College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.|Center for Quantitative Biology, Peking University, Beijing 100871, China.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Beijing Nuclear Magnetic Resonance Center, Peking University, Beijing 100871, China.|College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
authors.forename: Changwen
authors.initials: C
authors.lastname: Jin
authors.affiliation: BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.|Center for Quantitative Biology, Peking University, Beijing 100871, China.|Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Luhua
authors.initials: L
authors.lastname: Lai
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000737:chemistry; D002474:Cell-Free System; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D018922:HL-60 Cells; D006801:Humans; D064267:Intrinsically Disordered Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D000072417:Protein Domains; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014584:User-Computer Interface
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D064267:Intrinsically Disordered Proteins; D016271:Proto-Oncogene Proteins c-myc