New Frontiers in Druggability.

Area of Science:

• Biophysics
• Computational Chemistry
• Drug Discovery

Background:

• Historically, Nuclear Magnetic Resonance (NMR)-based screening of small compound libraries was a key method for assessing protein druggability.
• This empirical approach relies on experimental screening to determine hit rates.

Purpose of the Study:

• To develop and validate a computational analog of NMR-based screening for protein druggability assessment.
• To explore the method's ability to provide meaningful insights beyond traditional drug-like compound limitations.

Main Methods:

• A computational method was developed based on mapping proteins using small molecules as probes.
• This approach models the biophysics of molecular binding.
• The method was applied to a large dataset of proteins.

Main Results:

• The computational method reliably reproduced druggability results obtained from NMR-based screening.
• The computational approach provided more meaningful assessments, particularly where NMR and computational predictions diverged.
• The method successfully identified protein targets not amenable to conventional drug-like compounds but potentially druggable by larger molecules like macrocycles.

Conclusions:

• The computational mapping method offers a robust and reliable alternative to experimental NMR screening for evaluating protein druggability.
• Its biophysics-based foundation allows for broader applicability, extending beyond conventionally druglike ligands to novel compound classes.
• This approach enhances the identification of novel therapeutic targets and expands the chemical space for drug development.