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Induced-Fit Docking Enables Accurate Free Energy Perturbation Calculations in Homology Models
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    Induced-Fit Docking Enables Accurate Free Energy Perturbation Calculations in Homology Models
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    Journal of Chemical Theory and Computation

    Cite this: J. Chem. Theory Comput. 2022, 18, 9, 5710–5724
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    https://doi.org/10.1021/acs.jctc.2c00371
    Published August 16, 2022
    Copyright © 2022 American Chemical Society

    Abstract

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    Homology models have been used for virtual screening and to understand the binding mode of a known active compound; however, rarely have the models been shown to be of sufficient accuracy, comparable to crystal structures, to support free-energy perturbation (FEP) calculations. We demonstrate here that the use of an advanced induced-fit docking methodology reliably enables predictive FEP calculations on congeneric series across homology models ≥30% sequence identity. Furthermore, we show that retrospective FEP calculations on a congeneric series of drug-like ligands are sufficient to discriminate between predicted binding modes. Results are presented for a total of 29 homology models for 14 protein targets, showing FEP results comparable to those obtained using experimentally determined crystal structures for 86% of homology models with template structure sequence identities ranging from 30 to 50%. Implications for the use and validation of homology models in drug discovery projects are discussed.

    Copyright © 2022 American Chemical Society

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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.2c00371.

    • Detailed results for each homology modeling case and the individual poses generated by IFD-MD and GlideSP, parameter values for the composite scoring function, and congeneric subseries selected for PDE10A validation (PDF)

    • Coordinates of public retrospective predictions (ZIP)

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    Journal of Chemical Theory and Computation

    Cite this: J. Chem. Theory Comput. 2022, 18, 9, 5710–5724
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jctc.2c00371
    Published August 16, 2022
    Copyright © 2022 American Chemical Society

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