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<p>Retrosynthesis consists of recursively breaking down a target molecule to produce a synthesis route composed of readily accessible building blocks. In recent years, computer-aided synthesis planning methods have allowed a greater exploration of potential synthesis routes, combining state-of-the-art machine-learning methods with chemical knowledge. However, these methods are generally developed to produce individual routes from a singular product to a set of proposed building blocks and are not designed to leverage potential shared paths between targets. These methods do not necessarily encompass real-world use cases in medicinal chemistry, where one seeks to synthesize sets of target compounds in a library mode, looking for maximal convergence into a shared retrosynthetic path going via advanced key intermediate compounds. Using a graph-based processing pipeline, we explore Johnson &amp; Johnson Electronic Laboratory Notebooks (J&amp;J ELN) and publicly available datasets to identify complex routes with multiple target molecules sharing common intermediates, producing convergent synthesis routes. We find that over 70% of all reactions are involved in convergent synthesis, covering over 80% of all projects in the case of J&amp;J ELN data. </p><p><b>Scientific contribution</b></p><p>We introduce a novel planning approach to develop convergent synthesis routes, which can search multiple products and intermediates simultaneously guided by state-of-the-art machine learning single-step retrosynthesis models, enhancing the overall efficiency and practical applicability of retrosynthetic planning. We evaluate the multi-step synthesis planning approach using the extracted convergent routes and observe that solvability is generally high across those routes, being able to identify a convergent route for over 80% of the test routes and showing an individual compound solvability of over 90%. We find that by using a convergent search approach, we can synthesize almost 30% more compounds simultaneously for J&amp;J ELN as compared to using an individual search, while providing an increased use of common intermediates.</p>

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Improving route development using convergent retrosynthesis planning

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年2月27日

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  • Paula Torren-Peraire,
  • Jonas Verhoeven,
  • Dorota Herman,
  • Hugo Ceulemans,
  • Igor V. Tetko,
  • Jörg K. Wegner

摘要

Retrosynthesis consists of recursively breaking down a target molecule to produce a synthesis route composed of readily accessible building blocks. In recent years, computer-aided synthesis planning methods have allowed a greater exploration of potential synthesis routes, combining state-of-the-art machine-learning methods with chemical knowledge. However, these methods are generally developed to produce individual routes from a singular product to a set of proposed building blocks and are not designed to leverage potential shared paths between targets. These methods do not necessarily encompass real-world use cases in medicinal chemistry, where one seeks to synthesize sets of target compounds in a library mode, looking for maximal convergence into a shared retrosynthetic path going via advanced key intermediate compounds. Using a graph-based processing pipeline, we explore Johnson & Johnson Electronic Laboratory Notebooks (J&J ELN) and publicly available datasets to identify complex routes with multiple target molecules sharing common intermediates, producing convergent synthesis routes. We find that over 70% of all reactions are involved in convergent synthesis, covering over 80% of all projects in the case of J&J ELN data.

Scientific contribution

We introduce a novel planning approach to develop convergent synthesis routes, which can search multiple products and intermediates simultaneously guided by state-of-the-art machine learning single-step retrosynthesis models, enhancing the overall efficiency and practical applicability of retrosynthetic planning. We evaluate the multi-step synthesis planning approach using the extracted convergent routes and observe that solvability is generally high across those routes, being able to identify a convergent route for over 80% of the test routes and showing an individual compound solvability of over 90%. We find that by using a convergent search approach, we can synthesize almost 30% more compounds simultaneously for J&J ELN as compared to using an individual search, while providing an increased use of common intermediates.