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Fragment-Based Discovery and Optimization of Enzyme Inhibitors by Docking of Commercial Chemical Space

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Department of Biochemistry and Biophysics, Stockholm University, SE-106 91 Stockholm, Sweden
Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Box 1031, SE-171 21 Solna, Sweden
§ Science for Life Laboratory, Department of Cell and Molecular Biology, BMC, Uppsala University, Box 596, SE-751 24 Uppsala, Sweden
Cite this: J. Med. Chem. 2017, 60, 19, 8160–8169
Publication Date (Web):September 20, 2017
Copyright © 2017 American Chemical Society

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    Abstract Image

    Fragment-based lead discovery has emerged as a leading drug development strategy for novel therapeutic targets. Although fragment-based drug discovery benefits immensely from access to atomic-resolution information, structure-based virtual screening has rarely been used to drive fragment discovery and optimization. Here, molecular docking of 0.3 million fragments to a crystal structure of cancer target MTH1 was performed. Twenty-two predicted fragment ligands, for which analogs could be acquired commercially, were experimentally evaluated. Five fragments inhibited MTH1 with IC50 values ranging from 6 to 79 μM. Structure-based optimization guided by predicted binding modes and analogs from commercial chemical libraries yielded nanomolar inhibitors. Subsequently solved crystal structures confirmed binding modes predicted by docking for three scaffolds. Structure-guided exploration of commercial chemical space using molecular docking gives access to fragment libraries that are several orders of magnitude larger than those screened experimentally and can enable efficient optimization of hits to potent leads.

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.7b01006.

    • Additional data and methods (PDF)

    • Molecular formula strings (CSV)

    • Atomic coordinates of predicted binding modes of fragments 15 (ZIP)

    Accession Codes

    Atomic coordinates of MTH1 bound to compounds 1a, 2, and 4b (PDB codes 5NGS, 5NGR, and 5NGT) have been deposited in the Protein Data Bank. Authors will release atomic coordinates and experimental data upon article publication.

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    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system:

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