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Proteolysis-targeting chimeras (PROTACs) require cell permeability for efficacy. Flexible PROTACs with folded conformations and low polar surface area exhibit enhanced cell permeability, guiding future PROTAC design.

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Area of Science:

  • Medicinal Chemistry
  • Chemical Biology
  • Computational Chemistry

Background:

  • Proteolysis-targeting chimeras (PROTACs) are bifunctional molecules designed to induce targeted protein degradation.
  • Achieving sufficient cell permeability for PROTACs is a significant challenge due to their large molecular size and complex structures, often exceeding traditional drug-like properties.
  • Understanding the physicochemical factors governing PROTAC cell permeability is crucial for their development as therapeutic agents.

Purpose of the Study:

  • To investigate the structural determinants of cell permeability in flexible cereblon-binding PROTACs.
  • To elucidate the relationship between PROTAC conformation, solvent-accessible surface area, and cell permeability.
  • To evaluate the utility of computational methods for predicting PROTAC cell permeability.

Main Methods:

  • Utilized Nuclear Magnetic Resonance (NMR) spectroscopy to analyze the conformational properties of PROTACs in solution.
  • Employed molecular dynamics (MD) simulations to model and assess PROTAC conformations and their interactions in different environments.
  • Correlated observed conformational preferences and physicochemical properties with experimentally determined cell permeability data.

Main Results:

  • Both NMR spectroscopy and MD simulations indicated that PROTACs with a propensity to adopt folded conformations in apolar environments exhibit higher cell permeability.
  • A low solvent-accessible 3D polar surface area in folded PROTAC conformations was identified as a key factor for enhanced cell penetration.
  • Linker chemical nature and flexibility were critical for enabling the formation of folded structures stabilized by intramolecular interactions (hydrogen bonds, π-π, van der Waals).

Conclusions:

  • The ability of PROTACs to adopt compact, folded conformations is directly linked to their cell permeability.
  • Intramolecular interactions play a vital role in stabilizing these permeability-enhancing conformations.
  • MD simulations show promise as a predictive tool for optimizing PROTAC design and ranking cell permeability prospects.