Pharmacophore model of the quercetin binding site of the SIRT6 protein.
SIRT6 is a histone deacetylase that has been proposed as a potential therapeutic target for metabolic disorders and the prevention of age-associated diseases. We have previously reported on the identification of quercetin and vitexin as SIRT6 inhibitors, and studied structurally related flavonoids including luteolin, kaempferol, apigenin and naringenin. It was determined that the SIRT6 protein remained active after immobilization and that a single frontal displacement could correctly predict the functional activity of the immobilized enzyme. The previous study generated a preliminary pharmacophore for the quercetin binding site on SIRT6, containing 3 hydrogen bond donors and one hydrogen bond acceptor. In this study, we have generated a refined pharmacophore with an additional twelve quercetin analogs. The resulting model had a positive linear behavior between the experimental elution time verses the fit values obtained from the model with a correlation coefficient of 0.8456.
Advanced Biomedical Computing Center, SAIC-Frederick, Inc., Information Systems Program, Frederick National Laboratory for Cancer Research (FNLCR), Frederick, MD 21702, USA.
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Ravichandran
Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, NIH, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
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Singh
School of Chemistry, University of Leeds, Leeds LS2 9JT, UK.
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Donnelly
School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK.
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Migliore
School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK.
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Johnson
School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK.
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Fishwick
Advanced Biomedical Computing Center, SAIC-Frederick, Inc., Information Systems Program, Frederick National Laboratory for Cancer Research (FNLCR), Frederick, MD 21702, USA.
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Luke
Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, NIH, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
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Martin
Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, NIH, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
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Maudsley
Department of Biomedical Sciences, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Taiwan.
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Fugmann
Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, NIH, 251 Bayview Boulevard, Baltimore, MD 21224, USA. Electronic address: moaddelru@mail.nih.gov.
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Moaddel
D001665:Binding Sites; D006801:Humans; D006860:Hydrogen Bonding; D011794:Quercetin / Q000737:chemistry* / Q000378:metabolism*; D037761:Sirtuins / Q000737:chemistry* / Q000378:metabolism*
D011794:Quercetin; C516592:SIRT6 protein, human; D037761:Sirtuins
Frontal displacement chromatography; HAT; HDAC; Pharmacophore modeling; SIRT6