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dc.contributor.authorLin, F.-Y.
dc.contributor.authorMackerell, A.D.
dc.date.accessioned2019-09-19T18:35:47Z
dc.date.available2019-09-19T18:35:47Z
dc.date.issued2017
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85025579409&doi=10.1021%2facs.jpcb.7b04198&partnerID=40&md5=41eef0d00310e4e12ff73854bf227c61
dc.identifier.urihttp://hdl.handle.net/10713/10971
dc.description.abstractHalogens 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.en_US
dc.description.sponsorshipThis 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.en_US
dc.description.urihttps://doi.org/10.1021/acs.jpcb.7b04198en_US
dc.language.isoen_USen_US
dc.publisherAmerican Chemical Societyen_US
dc.relation.ispartofJournal of Physical Chemistry B
dc.subject.meshDatabases, Proteinen_US
dc.subject.meshHalogens--chemistryen_US
dc.subject.meshHalogens--metabolismen_US
dc.subject.meshHydrogen Bondingen_US
dc.subject.meshLigandsen_US
dc.subject.meshProtein Structure, Tertiaryen_US
dc.subject.meshProteins--chemistryen_US
dc.subject.meshProteins--metabolismen_US
dc.subject.meshQuantum Theoryen_US
dc.titleDo Halogen-Hydrogen Bond Donor Interactions Dominate the Favorable Contribution of Halogens to Ligand-Protein Binding?en_US
dc.typeArticleen_US
dc.identifier.doi10.1021/acs.jpcb.7b04198
dc.identifier.pmid28657759


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