Structure-based Inhibitor Design for the Intrinsically Disordered Protein c-Myc.
Sci Rep
; 6: 22298, 2016 Mar 02.
Article
in En
| MEDLINE
| ID: mdl-26931396
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.
Full text:
1
Database:
MEDLINE
Main subject:
Drug Design
/
Proto-Oncogene Proteins c-myc
/
Intrinsically Disordered Proteins
Type of study:
Prognostic_studies
Language:
En
Journal:
Sci Rep
Year:
2016
Type:
Article
Affiliation country:
China