A multifaceted secondary structure mimic based on piperidine-piperidinones.

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Computational Chemistry

Background:

• Minimalist secondary structure mimics typically target one protein-protein interaction (PPI) interface.
• A novel approach proposes matching suitable chemotypes directly with PPI interface regions, bypassing secondary structure considerations.

Purpose of the Study:

• To describe the modular synthesis of a new chemotype (1).
• To simulate its solution-state conformational ensemble and correlate it with ideal secondary structures and real PPI interface regions.
• To introduce a new method for assessing the relevance of crystal structures to solution conformations.

Main Methods:

• Modular synthesis of chemotype 1.
• Computational simulation of solution-state conformational ensemble.
• Correlation analysis between mimic conformations and PPI interfaces.
• Development of a method to evaluate crystal structure relevance to solution conformations.

Main Results:

• Scaffold 1 presents amino acid side-chains in orientations mimicking ideal sheet/helical structures and non-ideal PPI interfaces.
• Conformations of scaffold 1 showed good matches with 68 different PPIs.
• A method was developed to assess crystal structure relevance to solution conformations, showing DLD-1 faf crystallized above its minimum energy solution state.

Conclusions:

• Chemotype 1 serves as a versatile scaffold for mimicking diverse PPI interfaces.
• The developed methods enhance the understanding of molecular mimicry in drug design.
• This approach offers new possibilities for perturbing PPIs and developing therapeutics.