Recore: a fast and versatile method for scaffold hopping based on small molecule crystal structure conformations.

Area of Science:

• Computational chemistry
• Medicinal chemistry
• Drug discovery

Background:

• Scaffold replacement is crucial for discovering new compound classes.
• Existing computational methods vary in input, similarity measures, and replacement descriptions.
• There is a need for tools that avoid strained conformations, explore large search spaces, and offer short response times.

Purpose of the Study:

• To introduce a novel scaffold replacement approach and software tool, Recore.
• To combine avoidance of strained conformations, large search space exploration, and interactive use with short response times.
• To present a new technique using 3D fragments generated by combinatorial enumeration of cuts.

Main Methods:

• Developed Recore software utilizing a novel scaffold replacement technique.
• Employed combinatorial enumeration of cuts to generate 3D fragments.
• Utilized a geometric rank searching algorithm with exit vectors and pharmacophore features.

Main Results:

• The Recore approach successfully focuses on fragments suitable for scaffold replacement.
• Conformational information from crystal structures is retained.
• The algorithm identifies fragments based on geometric constraints and pharmacophore features, ordered by deviation.
• Validation across three design scenarios demonstrated the approach's ability to propose new, valid scaffold topologies.

Conclusions:

• The Recore approach offers an effective method for scaffold replacement in drug discovery.
• The tool facilitates the exploration of novel chemical entities by generating valid scaffold topologies.
• Recore addresses limitations of previous methods by integrating conformational stability, search space efficiency, and interactive performance.