LeadOp+R: Structure-Based Lead Optimization With Synthetic Accessibility.

Area of Science:

• Computational chemistry
• Medicinal chemistry
• Drug discovery

Background:

• Structure-based fragment hopping (LeadOp) optimizes ligands by replacing fragments.
• LeadOp improves compound activity but faces synthetic challenges.
• Integrating synthetic accessibility is crucial for efficient lead optimization.

Purpose of the Study:

• To develop LeadOp+R, a novel method for structure-based lead optimization that incorporates synthetic accessibility.
• To systematically generate improved drug analogs with feasible synthetic routes.

Main Methods:

• LeadOp+R utilizes a database of 198 chemical reactions to guide fragment hopping.
• It preserves a defined molecular space and grows molecules towards favorable receptor-ligand interactions.
• Multiple conformers are evaluated at each step to select the most efficient building blocks.

Main Results:

• LeadOp+R successfully optimized query molecules for Tie-2 kinase and human 5-lipoxygenase.
• The method generated improved analogs with systematically designed synthetic routes.
• Proposed synthetic routes matched those developed by expert chemists.

Conclusions:

• LeadOp+R effectively combines lead optimization with synthetic route planning.
• This approach enhances the feasibility of fragment-based drug design.
• LeadOp+R accelerates the drug discovery process by providing synthetically viable optimized compounds.