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Front. Pharmacol. | doi: 10.3389/fphar.2018.00096

LeadOp+R: Structure-based lead optimization with synthetic accessibility

 Yufeng J. Tseng1, 2*,  Emilio Esposito3 and Fang-yu Lin1
  • 1Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taiwan
  • 2Department of Computer Science and Information Engingeering, National Taiwan University, Taiwan
  • 3exeResearch LLC, United States

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 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 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.

Keywords: Fragment-based, lead optimization, structure-based drug design, Computer-assisted Synthesis, Human 5-Lipoxygenase, Tie-2 kinase

Received: 28 Sep 2017; Accepted: 29 Jan 2018.

Edited by:

Leonardo G. Ferreira, University of São Paulo, Brazil

Reviewed by:

Alain Couvineau, Institut National de la Santé et de la Recherche Médicale (INSERM), France
Yingxia Li, Fudan University, China  

Copyright: © 2018 Tseng, Esposito and Lin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Yufeng J. Tseng, National Taiwan University, Graduate Institute of Biomedical Electronics and Bioinformatics, Taipei, Taiwan,