SHOP: a method for structure-based fragment and scaffold hopping.

Area of Science:

• Computational chemistry
• Medicinal chemistry
• Drug discovery

Background:

• Fragment-based drug design is a key strategy in discovering novel therapeutics.
• Existing methods may lack precision in targeted molecular modification.
• The need for efficient and accurate fragment replacement techniques is critical.

Purpose of the Study:

• To present a new computational methodology for fragment and scaffold replacement in drug discovery.
• To validate the method's efficacy in generating biologically active compounds.
• To optimize the method by investigating key customizable parameters.

Main Methods:

• Utilizing GRID molecular interaction fields (MIFs) and target crystal structures.
• Focusing on replacing specific molecular fragments while preserving essential binding elements.
• Employing 164 fragment queries across 11 diverse targets for validation.

Main Results:

• The method successfully recovered up to 95% of original fragments within the top-five solutions.
• Filtering receptor MIFs by co-crystallized ligand atom type significantly impacted solution ranking.
• Application to realistic scenarios yielded diverse chemotypes, including known target binders.

Conclusions:

• The presented fragment replacement method effectively generates novel compound families with biological activity.
• The methodology offers a targeted approach to drug design, distinct from traditional virtual screening.
• Optimized parameter selection enhances the reliability and diversity of generated drug candidates.