Inhibiting a promiscuous GPCR: iterative discovery of bitter taste receptor ligands
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Abstract
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The single homology model (HM0) was evaluated in its ability to discriminate agonists and antagonists from decoys, obtaining EF value for agonists discrimination slightly better than AF0 and IT0 (Fig. 2) and the top AUC registered within the models of this study. On the other hand, poor results are obtained for the antagonist model.
This is interesting and highlights the utility of this work.
This is an archived comment originally written by Peter Thuy-Boun
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Superposition between IT3+ in complex with flufenamic acid (both in green licorice) and IT3-in complex with the flufenamic acid derivative antagonist LW131 (both in orange licorice). The two ligands overlap within the binding site. The H-bond interaction observed only in the IT3+ between 3.36 and 6.48 is shown as a yellow dotted line and it is potentially affected by the presence of the para substituent on ring B (orange transparent circle) of the antagonist.
Just a minor suggestion: the 4-chloro substituent in the antagonist molecule is a little difficult to discern in figure 3b because the 4-chloro group is a similar color to the carbon skeleton of the overlapping flufenamic acid agonist. Changing the 4-chloro group to a more distinct color would be helpful.
This is an archived comment originally written by Peter Thuy-Boun
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In an extensive TAS2R14 mutagenesis study, Nowak et al suggested that flufenamic acid and aristolochic acid bind differently in the receptor-binding pocket
Would it be possible to generate hypothetical models for aristolochic acid binding using techniques employed in this study?
This is an archived comment originally written by Peter Thuy-Boun
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Among the antagonists with novel scaffolds discovered through the computational study, LF1, LF14, and LF22 were able to reduce the activity of the receptor and block flufenamic acid induced TAS2R14 activity with a half-maximal inhibitory concentration of 6.8±3.2, 22±16 and 7.2±3μM, respectively
Being able to tolerate a two atom bridge between the two key aromatic rings would increase antagonist diversity (LF1, LF14). LF22 is also interesting as there doesn't seem to be a strict requirement that there are two closely bridged aromatic rings in the inhibitor backbone. Was LF22 tested in racemic form? If so, is one isomer expected to be a better inhibitor than the other?
This is an archived comment originally written by Peter Thuy-Boun
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Table 2
Can you provide some commentary about why LW209 and LW145 appear to be similarly effective in the antagonist assay but LW209 appears to be an order of magnitude more effective (as an inhibitor) in the agonist assay? Is this just an assay artifact?
This is an archived comment originally written by Peter Thuy-Boun
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Among the antagonists with novel scaffolds discovered through the computational study, LF1, LF14, and LF22 were able to reduce the activity of the receptor and block flufenamic acid induced TAS2R14 activity with a half-maximal inhibitory concentration of 6.8±3.2, 22±16 and 7.2±3μM, respectively
Being able to tolerate a two atom bridge between the two key aromatic rings would increase antagonist diversity (LF1, LF14). LF22 is also interesting as there doesn't seem to be a strict requirement that there are two closely bridged aromatic rings in the inhibitor backbone. Was LF22 tested in racemic form? If so, is one isomer expected to be a better inhibitor than the other?
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The single homology model (HM0) was evaluated in its ability to discriminate agonists and antagonists from decoys, obtaining EF value for agonists discrimination slightly better than AF0 and IT0 (Fig. 2) and the top AUC registered within the models of this study. On the other hand, poor results are obtained for the antagonist model.
This is interesting and highlights the utility of this work.
-
Superposition between IT3+ in complex with flufenamic acid (both in green licorice) and IT3-in complex with the flufenamic acid derivative antagonist LW131 (both in orange licorice). The two ligands overlap within the binding site. The H-bond interaction observed only in the IT3+ between 3.36 and 6.48 is shown as a yellow dotted line and it is potentially affected by the presence of the para substituent on ring B (orange transparent circle) of the antagonist.
Just a minor suggestion: the 4-chloro substituent in the antagonist molecule is a little difficult to discern in figure 3b because the 4-chloro group is a similar color to the carbon skeleton of the overlapping flufenamic acid agonist. Changing the 4-chloro group to a more distinct color would be helpful.
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In an extensive TAS2R14 mutagenesis study, Nowak et al suggested that flufenamic acid and aristolochic acid bind differently in the receptor-binding pocket
Would it be possible to generate hypothetical models for aristolochic acid binding using techniques employed in this study?
-
(Table 2
Can you provide some commentary about why LW209 and LW145 appear to be similarly effective in the antagonist assay but LW209 appears to be an order of magnitude more effective (as an inhibitor) in the agonist assay? Is this just an assay artifact?
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