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

Area of Science:

• Biochemistry
• Computational Biology
• Drug Discovery

Background:

• Intrinsically disordered proteins (IDPs) are implicated in diseases but challenging for drug discovery due to their lack of fixed structures.
• Conventional structure-based drug design methods are ineffective for IDPs.

Purpose of the Study:

• To develop and validate a novel computational approach for virtual screening of compounds against multiple conformations of IDPs.
• To identify potential drug candidates targeting the oncoprotein c-Myc, a representative IDP.

Main Methods:

• Developed a computational strategy involving IDP conformation sampling and binding site identification.
• Performed virtual screening of compounds against three distinct binding pockets in representative c-Myc conformations.
• Validated compound binding and cellular effects in vitro and in cell-based assays.

Main Results:

• Identified seven compounds that directly bind to c-Myc370-409 in vitro.
• Four of the identified compounds inhibited the growth of c-Myc-overexpressing cancer cells.
• Demonstrated that the compounds affect cell cycle progression.

Conclusions:

• The novel computational approach enables structure-based drug discovery for IDPs by considering multiple conformations.
• This strategy offers a viable pathway for developing therapeutics against IDP-associated diseases, exemplified by targeting c-Myc.