Exploring key orientations at protein-protein interfaces with small molecule probes.

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Drug Discovery

Background:

• Protein-protein interactions (PPIs) are crucial in biological processes, and small molecules that modulate them are valuable biomedical tools.
• Discovering selective small molecule probes for PPIs remains a significant challenge in drug development.

Purpose of the Study:

• To develop and validate a novel computational approach for identifying small molecule scaffolds that can perturb PPIs.
• To design and synthesize molecules based on this approach and test their efficacy against a specific PPI target.

Main Methods:

• A data mining algorithm was employed to identify PPIs with conformational similarities to semirigid molecular scaffolds.
• A specific chemotype (1aaa) was selected, and its preferred conformers were computationally matched against known PPI interfaces.
• Four candidate molecules were synthesized based on the identified matches to the HIV-1 protease dimerization interface.

Main Results:

• The computational approach successfully identified conformational matches between the selected scaffold and several significant PPIs, including the HIV-1 protease dimerization interface.
• All four synthesized molecules demonstrated inhibition of HIV-1 protease activity.
• The inhibition was attributed to the perturbation of the protein-protein dimerization process.

Conclusions:

• The study presents a promising strategy for the rational design of small molecule probes targeting PPIs.
• This data-mining-guided approach can accelerate the discovery of novel inhibitors for challenging biological targets.
• The findings may inspire the development of new therapeutic agents by targeting protein-protein interactions.