EHreact: Extended Hasse Diagrams for the Extraction and Scoring of Enzymatic Reaction Templates.

Esther Heid,William H Green,Connor W Coley,Karthik Sankaranarayanan,Christoph Flamm,Samuel Goldman

doi:10.1021/acs.jcim.1c00921

Esther Heid, William H Green + Show 4 more

Open Access

https://doi.org/10.1021/acs.jcim.1c00921

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Abstract

Data-driven computer-aided synthesis planning utilizing organic or biocatalyzed reactions from large databases has gained increasing interest in the last decade, sparking the development of numerous tools to extract, apply, and score general reaction templates. The generation of reaction rules for enzymatic reactions is especially challenging since substrate promiscuity varies between enzymes, causing the optimal levels of rule specificity and optimal number of included atoms to differ between enzymes. This complicates an automated extraction from databases and has promoted the creation of manually curated reaction rule sets. Here, we present EHreact, a purely data-driven open-source software tool, to extract and score reaction rules from sets of reactions known to be catalyzed by an enzyme at appropriate levels of specificity without expert knowledge. EHreact extracts and groups reaction rules into tree-like structures, Hasse diagrams, based on common substructures in the imaginary transition structures. Each diagram can be utilized to output a single or a set of reaction rules, as well as calculate the probability of a new substrate to be processed by the given enzyme by inferring information about the reactive site of the enzyme from the known reactions and their grouping in the template tree. EHreact heuristically predicts the activity of a given enzyme on a new substrate, outperforming current approaches in accuracy and functionality.

Highlights

If the atom-mapping is not known, it is automatically calculated via the Reaction Decoder Tool[37] (RDT), a state-of-the-art tool for atommapping enzymatic reactions.[38]
We have introduced a novel method of extracting multiple reaction templates from a set of known reactions and utilizing the mutual information between them to obtain better predictions of the activity of non-natural substrates
EHreact allows for the extraction of single, unique, and mutually exclusive templates at a level of specificity imposed by the set of input reaction, whereas conventional extraction routines lead to multiple, sometimes not mutually exclusive templates and require user-defined criteria of how many atoms to include

Summary

Introduction

Biocatalytic transformations nowadays comprise an everexpanding toolbox of chemo-, stereo-, and regioselective reactions.[1−7] The use of enzymes to catalyze reactions has several benefits, such as mild reaction conditions, aqueous media as solvents, compatibility of different reaction steps in multistep syntheses, as well as the reduced need for protecting groups.[3,4,8] Most enzymes are promiscuous to at least some extent or can be engineered to accept a new substrate, so that the possible range of biocatalyzed transformations is large enough to be of interest to synthetic chemists, as testified by the large number of novel enzymatic cascades for the synthesis of diverse targets that were published in the last decade.[2,3,6,7,9−15] Enzymatic transformations provide a promising and ecofriendly alternative to organic reactions in the synthesis of pharmaceutical intermediates or fine chemicals, among others.[2]In practice, moderately promiscuous enzymes are often preferred when designing a pathway, where a small amount of activity can be increased via directed evolution.[16]. Biocatalytic transformations nowadays comprise an everexpanding toolbox of chemo-, stereo-, and regioselective reactions.[1−7] The use of enzymes to catalyze reactions has several benefits, such as mild reaction conditions, aqueous media as solvents, compatibility of different reaction steps in multistep syntheses, as well as the reduced need for protecting groups.[3,4,8] Most enzymes are promiscuous to at least some extent or can be engineered to accept a new substrate, so that the possible range of biocatalyzed transformations is large enough to be of interest to synthetic chemists, as testified by the large number of novel enzymatic cascades for the synthesis of diverse targets that were published in the last decade.[2,3,6,7,9−15] Enzymatic transformations provide a promising and ecofriendly alternative to organic reactions in the synthesis of pharmaceutical intermediates or fine chemicals, among others.[2]. We will only refer to substrate promiscuity

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