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

We previously described a structure-based fragment hopping for lead optimization using a pre-docked fragment database, “LeadOp,” that conceptually replaced “bad” fragments of a ligand with “good” fragments while leaving the core of the ligand intact thus improving the compound's activity. LeadOp was proven to optimize the query molecules and systematically developed improved analogs for each of our example systems. However, even with the fragment-based design from common building blocks, it is still a challenge for synthesis. In this work, “LeadOp+R” was developed based on 198 classical chemical reactions to consider the synthetic accessibility while optimizing leads. LeadOp+R first allows user to identify a preserved space defined by the volume occupied by a fragment of the query molecule to be preserved. Then LeadOp+R searches for building blocks with the same preserved space as initial reactants and grows molecules toward the preferred receptor-ligand interactions according to reaction rules from reaction database in LeadOp+R. Multiple conformers of each intermediate product were considered and evaluated at each step. The conformer with the best group efficiency score would be selected as the initial conformer of the next building block until the program finished optimization for all selected receptor-ligand interactions. The LeadOp+R method was tested with two biomolecular systems: Tie-2 kinase and human 5-lipoxygenase. The LeadOp+R methodology was able to optimize the query molecules and systematically developed improved analogs for each of our example systems. The suggested synthetic routes for compounds proposed by LeadOp+R were the same as the published synthetic routes devised by the synthetic/organic chemists.