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    Do Halogen-Hydrogen Bond Donor Interactions Dominate the Favorable Contribution of Halogens to Ligand-Protein Binding?

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    Author
    Lin, F.-Y.
    Mackerell, A.D.
    Date
    2017
    Journal
    Journal of Physical Chemistry B
    Publisher
    American Chemical Society
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1021/acs.jpcb.7b04198
    Abstract
    Halogens are present in a significant number of drugs, contributing favorably to ligand-protein binding. Currently, the contribution of halogens, most notably chlorine and bromine, is largely attributed to halogen bonds involving favorable interactions with hydrogen bond acceptors. However, we show that halogens acting as hydrogen bond acceptors potentially make a more favorable contribution to ligand binding than halogen bonds based on quantum mechanical calculations. In addition, bioinformatics analysis of ligand-protein crystal structures shows the presence of significant numbers of such interactions. It is shown that interactions between halogens and hydrogen bond donors (HBDs) are dominated by perpendicular C-X?HBD orientations. Notably, the orientation dependence of the halogen-HBD (X-HBD) interactions is minimal over greater than 100° with favorable interaction energies ranging from -2 to -14 kcal/mol. This contrasts halogen bonds in that X-HBD interactions are substantially more favorable, being comparable to canonical hydrogen bonds, with a smaller orientation dependence, such that they make significant, favorable contributions to ligand-protein binding and, therefore, should be actively considered during rational ligand design.
    Sponsors
    This work was supported by National Institutes of Health grants GM070855 and GM072558. The University of Maryland Computer-Aided Drug Design Center and XSEDE are acknowledged for their generous allocations of computer time.
    Keyword
    Databases, Protein
    Halogens--chemistry
    Halogens--metabolism
    Hydrogen Bonding
    Ligands
    Protein Structure, Tertiary
    Proteins--chemistry
    Proteins--metabolism
    Quantum Theory
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85025579409&doi=10.1021%2facs.jpcb.7b04198&partnerID=40&md5=41eef0d00310e4e12ff73854bf227c61; http://hdl.handle.net/10713/10971
    ae974a485f413a2113503eed53cd6c53
    10.1021/acs.jpcb.7b04198
    Scopus Count
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    UMB Open Access Articles 2017

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