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Case study: Empowering chemistry research with Synthia


The latest iteration of Merck’s flagship retrosynthesis design


software, Synthia, has been developed to give chemists the freedom to generate a synthetic route for just about any desired chemical compound. It does this while meeting specific criteria for that synthetic pathway, from the availability and cost of starting materials, to the avoidance of hazardous reaction steps or intermediates. ‘Synthia is uniquely founded on more than 100,000 reaction rules that have been coded by expert chemists,’ explained Dr Ewa Gajewska, chemistry development manager at Merck KGaA, Darmstadt, Germany, who has played a key role in development of the Synthia retrosynthesis software. ‘Whereas automated


retrosynthesis platforms commonly utilise data extracted from the literature, Gajewska notes, Synthia is unique in that it combines expert knowledge with the algorithms strategising over multiple steps, as well as modules and filters based on computational methods. ‘The latest release promises to further speed the derivation of efficient, reproducible synthetic pathways,’ she said. ‘We have, for example, witnessed the power of Synthia retrosynthesis software deployed globally by researchers in designing synthetic routes for potential Covid-19 therapeutics.’ Retrosynthesis is not a novel


concept. Chemists looking to synthesise a compound will commonly start at the final molecule and backtrack through reactions to identify starting compounds, or building blocks. While this had traditionally been a time-consuming, trial-and- error process to find a route that is feasible in the lab, and at larger scale, the evolution of AI algorithms and massive computing power has led to the


development of in silico solutions that can evaluate pathways in parallel, dramatically cutting the time required to create synthetic routes that meet all the process requirements and endpoints. Synthia retrosynthesis


software can rapidly evaluate and define dozens or more of the most likely practicable synthetic pathways for a molecule, whether that molecule has been previously described, or is completely novel. The platform can also be used to design new, faster, more efficient or more cost-effective synthetic approaches for existing drugs, for example, to match increased demand. ‘Taking into account chemical features, such as stereochemistry and the need to protect certain functional groups along the synthetic pathways, users can also hone down the number of potential pathways by applying conditions that, for example, may specify starting reagents, mandate cost restrictions or limit the number of reaction steps,’ Gajewska stated. ‘Because our database of reaction rules was coded by the expert chemists based on the underlying reaction mechanisms and considers stereo- and regiochemistry, as well as the context information, chemists can be confident that the pathways proposed are chemically feasible, and actionable in real-world settings.’ Training algorithms to


computationally contrive efficient organic synthetic pathways has, in fact, been a challenge for decades, Gajewska commented, and Synthia is the culmination of efforts to develop a platform that could take into account real-life constraints chemists face at the bench. ‘We’ve been able to harness the power of computers to embrace natural, reaction-related constraints, in parallel with other user-defined filters, to define


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the best routes in the shortest timeframe, which are ultimately based on chemical logic.’ These constraints may


include, for example, finding the shortest, enantioselective route that utilises building blocks available in the user’s inventory. A foundation on native ‘human’ understanding of each reaction mechanism allows Synthia retrosynthesis software to capture all of the nuances of chemical reactivity. ‘For example, the software considers the electronic and steric effects of the substituents that influence the reaction outcome,’ Gajewska noted. ‘Every reaction rule is also accompanied with the list of functional groups that are incompatible with these reactions, and the ones that will need protection.’ This marriage between expert human knowledge, algorithms


pointed out. ‘With the latest release, users will find improved pathway visualisation features that really help the chemist to choose the most promising pathway and start the synthesis.’ New features of the latest


Synthia retrosynthesis software release include: • Certification to ISO27001 standard for an independently verified information security management system (ISMS)


• Single sign-on • Incorporates 845 new reaction rules, plus integration with DeepMatter’s SPRESI database, which contains 4.6 mln reactions and 700,000 literature references for known reactions


• Interface allows users to search according to preset parameters, or customise and save their own parameters


• Filter results to favour pathways using preferred reactions, starting materials or intermediates


• Screen results to remove pathways with unwanted reactions, focus on interesting intermediates, or limit the number of protecting groups needed


“Synthia captures all of the nuances of chemical reactivity”


and computational methods is unique, Gajewska continued. ‘And it’s this combination of human- derived expertise and algorithms that allows the platform to accommodate such a wide range of user-defined expectations.’ Synthia retrosynthesis


software was originally developed at Grzybowski Scientific Inventions (GSI), and was acquired by Merck KGaA, Darmstadt, Germany, in 2017. Since then, continued R&D has resulted in the addition of new computational and search algorithms and expansion of the reaction rules database. ‘New synthetic methodologies are continually added,’ Gajewska


• Visualise results, including detailed schematic view of individual pathways, and structures, reaction names and conditions


• Easily build and save lists of molecules or functional groups to frequently favour or connect with scientific tools, using enhanced APIs for integrated workflow


Offered as a web-based platform via licence, Synthia retrosynthesis software also gives users the flexibility to effectively drive the retrosynthesis software manually, rather than rely on completely automated synthetic design. This means chemists can chart through pathways, starting with their end product, and work through stages backwards, much as chemists would do before in silico tools, but with the wealth of reaction details, references and other annotations for each reaction step they select, available at their fingertips.


Autumn 2021 Scientific Computing World 19


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