Rational modulator design by exploitation of protein-protein complex structures

Area of Science:

• Biochemistry
• Drug Discovery
• Structural Biology

Background:

• Protein-protein interactions (PPIs) are crucial in various diseases.
• Targeting PPIs offers a new frontier in drug discovery.
• Both globular and intrinsically disordered proteins mediate disease-relevant PPIs.

Purpose of the Study:

• To review experimental and computational methods for determining 3D structures of protein-protein complexes.
• To summarize structure-based approaches for designing PPI modulators.
• To illustrate rational and in silico design strategies for peptides, peptidomimetics, and small molecules.

Main Methods:

• Experimental techniques for 3D structure determination of protein complexes.
• Computational approaches for structure analysis and prediction.
• Structure-based molecular design principles.

Main Results:

• An overview of diverse methods for obtaining 3D protein-protein complex structures.
• Summary of strategies for designing PPI inhibitors and stabilizers.
• Illustration of rational and in silico design of PPI-modulating agents.

Conclusions:

• 3D structures of protein complexes are essential for rational drug design.
• Structure-based molecular design enables the development of novel PPI modulators.
• This review provides a guide to methods and strategies in PPI-targeted drug discovery.