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dc.contributor.author
Frey, Kathleen M.
dc.contributor.author
Gray, William T.
dc.contributor.author
Spasov, Krasimir A.
dc.contributor.author
Bollini, Mariela
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dc.contributor.author
Gallardo Macias, Ricardo
dc.contributor.author
Jorgensen, William L.
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Anderson, Karen S.
dc.date.available
2017-04-26T19:42:25Z
dc.date.issued
2014-05
dc.identifier.citation
Frey, Kathleen M.; Gray, William T.; Spasov, Krasimir A.; Bollini, Mariela; Gallardo Macias, Ricardo; et al.; Structure-based evaluation of C5 derivatives in the catechol diether series targeting HIV-1 reverse transcriptase; Wiley; Chemical Biology & Drug Design; 83; 5; 5-2014; 541-549
dc.identifier.issn
1747-0277
dc.identifier.uri
http://hdl.handle.net/11336/15764
dc.description.abstract
Using a computationally driven approach, a class of inhibitors with picomolar potency known as the catechol diethers were developed targeting the non-nucleoside-binding pocket of HIV-1 reverse transcriptase. Computational studies suggested that halogen-bonding interactions between the C5 substituent of the inhibitor and backbone carbonyl of conserved residue Pro95 might be important. While the recently reported crystal structures of the reverse transcriptase complexes confirmed the interactions with the non-nucleoside-binding pocket, they revealed the lack of a halogen-bonding interaction with Pro95. To understand the effects of substituents at the C5 position, we determined additional crystal structures with 5-Br and 5-H derivatives. Using comparative structural analysis, we identified several conformations of the ethoxy uracil dependent on the strength of a van der Waals interaction with the Cγ of Pro95 and the C5 substitution. The 5-Cl and 5-F derivatives position the ethoxy uracil to make more hydrogen bonds, whereas the larger 5-Br and smaller 5-H position the ethoxy uracil to make fewer hydrogen bonds. EC50 values correlate with the trends observed in the crystal structures. The influence of C5 substitutions on the ethoxy uracil conformation may have strategic value, as future derivatives can possibly be modulated to gain additional hydrogen-bonding interactions with resistant variants of reverse transcriptase.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Wiley
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
Halogen Bonds
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Hiv-1 Reverse Transcriptase
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Nonnucleoside Reverse Transcriptase Inhibitors
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Structure Activity Relationships
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Structure Based Drug Design
dc.subject.classification
Química Orgánica
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dc.subject.classification
Ciencias Químicas
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dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
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dc.title
Structure-based evaluation of C5 derivatives in the catechol diether series targeting HIV-1 reverse transcriptase
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2017-04-26T14:13:05Z
dc.journal.volume
83
dc.journal.number
5
dc.journal.pagination
541-549
dc.journal.pais
Estados Unidos
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dc.journal.ciudad
Hoboken
dc.description.fil
Fil: Frey, Kathleen M.. University of Yale; Estados Unidos
dc.description.fil
Fil: Gray, William T.. University of Yale; Estados Unidos
dc.description.fil
Fil: Spasov, Krasimir A.. University of Yale; Estados Unidos
dc.description.fil
Fil: Bollini, Mariela. University of Yale; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
dc.description.fil
Fil: Gallardo Macias, Ricardo. University of Yale; Estados Unidos
dc.description.fil
Fil: Jorgensen, William L.. University of Yale; Estados Unidos
dc.description.fil
Fil: Anderson, Karen S.. University of Yale; Estados Unidos
dc.journal.title
Chemical Biology & Drug Design
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/doi/10.1111/cbdd.12266/abstract
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1111/cbdd.12266
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