Structure-Based Lead Optimization with Synthetic Accessibility in Computer-Aided Drug Design
Date Issued
2011
Date
2011
Author(s)
Lin, Fang-Yu
Abstract
In this thesis, we describe two systems of structure based de novo optimization process, called “LeadOp” (short for Lead Optimization), and “LeadOp+R” (short for Lead Optimization with chemical Reaction).
In the first system, LeadOp, we described a structure based de novo optimization process, “LeadOp”, by decomposing a structure into fragments of different parts either by chemical rules or user-defined, evaluate each fragment at each part in a pre-docked fragment database that ranked fragments according to specific fragment-receptor binding interactions, replace fragments with less contribution to binding, and finally reassemble fragments from each part to form a ligand. The fundamental idea was to replace “bad” fragments of an inhibitor and replace with “good” fragments while leaving the rest of the inhibitor in the original core to improve the activity for lead optimization. The fragments were selected from a collection of 27,417 conformers by exhaustive docking at the target binding sites from synthesizable docked molecular building blocks and fragments from decomposing all known inhibitors from DrugBank database and related inhibitors. However, even with the fragment based design from common building blocks, it is still a challenge for synthesis. In the second system, “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 towards 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 two systems were examed with three biomolecular sysmtes, including mutant B-Raf kinase, Tie-2 kinase, and human 5-LOX inhibitor design. The “LeadOp” methodology was able to optimize the query molecules and systematically developed improved analogs for each of our example systems. The “LeadOp+R” methodology optimized the query molecule and systematically developed improved analogs along with their proposed synthetic routes. The suggested synthetic route (proposed from our synthesis algorithm) was the same as the published synthetic route devised by a synthetic/organic chemist.
Subjects
Fragment-based
Scaffold-Hopping
Lead Optimization
Structure-based Drug Design
Computer-aided Molecular Design
Computer-assisted Synthesis
Type
thesis
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