Probing biological mechanisms with chemical tools

Area of Science:

• Biochemistry
• Chemical Biology
• Drug Discovery

Background:

• Small molecules traditionally target protein biochemical activities.
• These molecules can also modulate protein conformational energy landscapes.
• Conformational modulation can uncover novel biological mechanisms with therapeutic implications.

Purpose of the Study:

• To explore the potential of small molecules in modulating protein conformations.
• To present examples of screening hits binding to unexpected protein pockets.
• To establish new strategies for inhibiting 'undruggable' proteins.

Main Methods:

• Screening of small molecule libraries.
• Identification of hits binding to novel allosteric sites.
• Characterization of protein-ligand interactions and functional consequences.

Main Results:

• Two examples demonstrating screening hits binding to unexpected pockets on known proteins.
• Discovery of new inhibition routes for previously intractable protein targets.
• Validation of the approach for identifying novel therapeutic strategies.

Conclusions:

• Small molecules offer a versatile approach to target protein conformation beyond traditional enzyme inhibition.
• Exploiting unexpected binding sites can overcome challenges posed by 'undruggable' targets.
• This strategy holds significant promise for advancing drug discovery and therapeutic development.