Route Designer: A Retrosynthetic Analysis Tool Utilizing Automated Retrosynthetic Rule Generation

Law, James; Zsoldos, Zsolt; Simon, Aniko; Reid, Darryl; Liu, Yang; Khew, Sing Yoong; Johnson, A. Peter; Major, Sarah; Wade, Robert A.; Ando, Howard Y.

doi:10.1021/ci800228y

Cited by 221 publications

(227 citation statements)

References 33 publications

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“…Finally,the idea of using similarity underlies the ARChem Route Designer [41] developed by SymBioSys.T his approach departs drastically from the concept of expert-coded reactions and instead relies on reaction transformations/reaction "rules" (close to 100 000) machine-extracted from similar literature examples (though it also supplies aset of around 50 hand-generated rules). Theprogram explores relatively short reaction trees exhaustively but does not account for stereochemistry and/or regiochemistry.I nasimilar genre,t he InfoChems IC SYNTH relies on the reaction cores extracted from various databases [42a] which are then used for construction of synthetic suggestion trees under user control.…”

Section: The Great Expectationsmentioning

confidence: 99%

“…[41,42] In such approaches,t he computer 1) extracts the group of atoms/ bonds that change in every reaction stored in the database and 2) possibly adds some predetermined number of flanking atoms to this "core" to define au nique synthetic transform. Unfortunately,there are major problems with such automatic extraction.…”

Section: No Easy Automationmentioning

confidence: 99%

“…All analysesw ere performed in Syntaurus with CSF = SMILES_LEN 3/2 + SMILES_LEN;R SF = 40 + 60·PROTECT + 50·CONFLICT 2 and tracing the searches to commercially available reagents with MW < 125. some relevant reaction rules/transforms were missing in the machines knowledge base (e.g., as in LHASA [5] or SYN-CHEM [8] ). In contrast, modern programs such as ARChem, [41] IC SYNTH , [42] or Syntaurus rely on complete or nearly complete reaction databases-where they go wrong is in predicting reactions which on paper might look acceptable but will not work in the laboratory.Aswenarrated earlier,the majority of these problems can be avoided at the level of properly coded reaction rules taking into account admissible substituents, stereochemistry,r egiochemistry,p rotection group chemistry and reactivity conflicts,aswell as electronic and most of steric effects,t he latter at the scale of the reaction motif being coded. Perhaps the hardest challenge is to account for steric effects in complex molecules whereby the entire threedimensional structure may dictate reactivity or its lack (Figure 23 and Ref.…”

Section: The Missing Versus Implausible Reaction Suggestions and Postmentioning

confidence: 99%

“…Such ac apability is largely missing in the existing software, and the user is either referred to the literature on "similar" reactions (ARChem, [41] IC SYNTH [42] )o rt ok ey publications describing agiven reaction type (Syntaurus). It has only been recently that progress has been made by the Va rneks group based on their Condensed Graph of Reaction (CGR) formalism.…”

Section: Predicting Reaction Conditionsmentioning

confidence: 99%

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Computer‐Assisted Synthetic Planning: The End of the Beginning

et al. 2016

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Exactly half a century has passed since the launch of the first documented research project (1965 Dendral) on computer-assisted organic synthesis. Many more programs were created in the 1970s and 1980s but the enthusiasm of these pioneering days had largely dissipated by the 2000s, and the challenge of teaching the computer how to plan organic syntheses earned itself the reputation of a "mission impossible". This is quite curious given that, in the meantime, computers have "learned" many other skills that had been considered exclusive domains of human intellect and creativity-for example, machines can nowadays play chess better than human world champions and they can compose classical music pleasant to the human ear. Although there have been no similar feats in organic synthesis, this Review argues that to concede defeat would be premature. Indeed, bringing together the combination of modern computational power and algorithms from graph/network theory, chemical rules (with full stereo- and regiochemistry) coded in appropriate formats, and the elements of quantum mechanics, the machine can finally be "taught" how to plan syntheses of non-trivial organic molecules in a matter of seconds to minutes. The Review begins with an overview of some basic theoretical concepts essential for the big-data analysis of chemical syntheses. It progresses to the problem of optimizing pathways involving known reactions. It culminates with discussion of algorithms that allow for a completely de novo and fully automated design of syntheses leading to relatively complex targets, including those that have not been made before. Of course, there are still things to be improved, but computers are finally becoming relevant and helpful to the practice of organic-synthetic planning. Paraphrasing Churchill's famous words after the Allies' first major victory over the Axis forces in Africa, it is not the end, it is not even the beginning of the end, but it is the end of the beginning for the computer-assisted synthesis planning. The machine is here to stay.

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Section: The Great Expectationsmentioning

confidence: 99%

Section: No Easy Automationmentioning

confidence: 99%

Section: The Missing Versus Implausible Reaction Suggestions and Postmentioning

confidence: 99%

Section: Predicting Reaction Conditionsmentioning

confidence: 99%

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Computer‐Assisted Synthetic Planning: The End of the Beginning

et al. 2016

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“…Retrosynthetic design starts by defining a target molecule of interest to produce and then 'walks' backwards through the known chemical transformation rules to modify the target molecule and identify potential precursors and reactions [8,9].…”

Section: Introductionmentioning

confidence: 99%

Design of computational retrobiosynthesis tools for the design of de novo synthetic pathways

Hadadi

Hatzimanikatis

2015

Current Opinion in Chemical Biology

118

106

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Designing putative metabolic pathways is of great interest in synthetic biology. Retrobiosynthesis is a discipline that involves the design, evaluation, and optimization of de novo biosynthetic pathways for the production of high-value compounds and drugs from renewable resources and natural or engineered enzymes. The best candidate pathways are then engineered within a metabolic network of microorganisms that serve as synthetic platforms for synthetic biology. The complexity of biological chemistry and metabolism requires computational approaches to explore the full possibilities of engineering synthetic pathways towards target compounds. Herein, we discuss recent developments in the design of computational tools for retrosynthetic biochemistry and outline the workflow and design elements for such tools.

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Automated Synthesis

Masquelin¹,

Kaerner²,

Bernhardt³

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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In a world where budgets and head counts are increasingly constrained and environmental impact scrutinized, new automated laboratory capabilities spanning from organic synthesis, analytical chemistry, through mechanical, chemical, and electrical engineering to robotics, computer science, and information technologies, are finding use as transformative methods for facilitating faster and better drug discovery operations as well as accelerated development of patient‐centric treatments and personalized medical applications. A significant challenge for life sciences researchers is gaining rapid access to probe molecules to query biological targets or pathways identified through various screening activities. Additional challenges include the ability to quickly and interactively optimize molecules identified as hits from screening activities. In the past two decades, the race has been on to build an automated laboratory to address gaps in organic synthesis and thereby supporting biological and drug discovery research by providing rapid access to a synthetic chemistry resource that is both cost‐effective and robust. This review focuses on concepts and approaches that have already been introduced in the automated synthesis world and also innovative technologies that could radically change small and large molecules research and, thus, have far‐reaching implications in the intelligent automation drug discovery world in the near future.

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Route Designer: A Retrosynthetic Analysis Tool Utilizing Automated Retrosynthetic Rule Generation

Cited by 221 publications

References 33 publications

Computer‐Assisted Synthetic Planning: The End of the Beginning

Computer‐Assisted Synthetic Planning: The End of the Beginning

Design of computational retrobiosynthesis tools for the design of de novo synthetic pathways

Automated Synthesis

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