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Large Computational Survey of Intrinsic Reactivity of Aromatic Carbon Atoms with Respect to a Model Aldehyde Oxidase

Cite this: J. Chem. Theory Comput. 2023, 19, 24, 9302–9317
Publication Date (Web):December 12, 2023
https://doi.org/10.1021/acs.jctc.3c00913
Copyright © 2023 American Chemical Society

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    Abstract

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    Aldehyde oxidase (AOX) and other related molybdenum-containing enzymes are known to oxidize the C–H bonds of aromatic rings. This process contributes to the metabolism of pharmaceutical compounds and, therefore, is of vital importance to drug pharmacokinetics. The present work describes an automated computational workflow and its use for the prediction of intrinsic reactivity of small aromatic molecules toward a minimal model of the active site of AOX. The workflow is based on quantum chemical transition state searches for the underlying single-step oxidation reaction, where the automated protocol includes identification of unique aromatic C–H bonds, creation of three-dimensional reactant and product complex geometries via a templating approach, search for a transition state, and validation of reaction end points. Conformational search on the reactants, products, and the transition states is performed. The automated procedure has been validated on previously reported transition state barriers and was used to evaluate the intrinsic reactivity of nearly three hundred heterocycles commonly found in approved drug molecules. The intrinsic reactivity of more than 1000 individual aromatic carbon sites is reported. Stereochemical and conformational aspects of the oxidation reaction, which have not been discussed in previous studies, are shown to play important roles in accurate modeling of the oxidation reaction. Observations on structural trends that determine the reactivity are provided and rationalized.

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jctc.3c00913.

    • X, Y, Z coordinates of 2089 TSs with the corresponding TS barriers in kcal/mol with respect to infinitely separated reactants (XYZ)

    • X, Y, Z coordinates of 2089 optimized reactant complexes, TSs, product complexes (6267 structures in total) with the corresponding gas phase energies in hartrees (XYZ)

    • Ensembles of isolated reactants (substrates only), TSs, and product complexes found during the conformational search stage and retained by our code. The energies in hartrees are given for each structure. Note that the ensembles for TSs 118-C, 201-H, 208-D, 322-F, 357-A, 389-C, and 390-C are missing for technical reasons (the TSs as well as other files for these data points are available in other *.xyz files in this Supporting Information) (XYZ)

    • Final optimized structures of the oxidized aromatic rings along with their energies in hartrees. The data are available for all structures used to construct Figure 12. Note that for pairs of enantiomer labeled, for example, A, B, only one (randomly chosen) structure is needed since the other structure would have the same energy (XYZ)

    • The optimized Mo-containing reactant and product molecules along with their energies in hartree (XYZ)

    • Analysis of the AOX structures from the Protein Data Bank, examples of correlations between ΔE and ΔG, absolute ranking of the regioselectivities of heterocycles, examples of a qualitative justification for the relative stabilities of two TS stereoisomers (PDF)

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