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Atomic basis for therapeutic activation of neuronal potassium channels.

Kim RY, Yau MC, Galpin JD, Seebohm G, Ahern CA, Pless SA, Kurata HT - Nat Commun (2015)

Bottom Line: Introduction of a non-natural isosteric H-bond-deficient Trp analogue abolishes channel potentiation, indicating that retigabine effects rely strongly on formation of a H-bond with the conserved pore Trp.In addition, potency of numerous retigabine analogues correlates with the negative electrostatic surface potential of a carbonyl/carbamate oxygen atom present in most KCNQ activators.These findings functionally pinpoint an atomic-scale interaction essential for effects of retigabine and provide stringent constraints that may guide rational improvement of the emerging drug class of KCNQ channel activators.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, 2176 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3.

ABSTRACT
Retigabine is a recently approved anticonvulsant that acts by potentiating neuronal M-current generated by KCNQ2-5 channels, interacting with a conserved Trp residue in the channel pore domain. Using unnatural amino-acid mutagenesis, we subtly altered the properties of this Trp to reveal specific chemical interactions required for retigabine action. Introduction of a non-natural isosteric H-bond-deficient Trp analogue abolishes channel potentiation, indicating that retigabine effects rely strongly on formation of a H-bond with the conserved pore Trp. Supporting this model, substitution with fluorinated Trp analogues, with increased H-bonding propensity, strengthens retigabine potency. In addition, potency of numerous retigabine analogues correlates with the negative electrostatic surface potential of a carbonyl/carbamate oxygen atom present in most KCNQ activators. These findings functionally pinpoint an atomic-scale interaction essential for effects of retigabine and provide stringent constraints that may guide rational improvement of the emerging drug class of KCNQ channel activators.

No MeSH data available.


Diverse structures of KCNQ openers.Multiple structures of KCNQ channel openers are presented to highlight the overall features of an amide group flanked by various ring structures. Our findings highlight the importance of the amide carbonyl for interaction with KCNQ3 Trp 265 and likely equivalent positions in KCNQ2, 4 and 5. Drugs depicted are (a) retigabine, (b) ztz-240 (described in ref. 24), (c) acrylamide (s)-1, (d) BMS-204352 and (e) an unnamed experimental drug described in ref. 43.
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f8: Diverse structures of KCNQ openers.Multiple structures of KCNQ channel openers are presented to highlight the overall features of an amide group flanked by various ring structures. Our findings highlight the importance of the amide carbonyl for interaction with KCNQ3 Trp 265 and likely equivalent positions in KCNQ2, 4 and 5. Drugs depicted are (a) retigabine, (b) ztz-240 (described in ref. 24), (c) acrylamide (s)-1, (d) BMS-204352 and (e) an unnamed experimental drug described in ref. 43.

Mentions: By demonstrating the effects of H-bond strength on a range of KCNQ3 activators, our findings suggest the importance of a carbonyl oxygen (usually in a carbamate or amide moiety) for the formation of a negative electrostatic surface potential to act as a H-bond acceptor. Previous screens of compound libraries have investigated important physicochemical features important for drug activity on KCNQ2–5 channels. Several studies have reported the importance of an amide bond (or a carbonyl oxygen) as an essential element of the pharmacophore, although the relationship between this functional group and the H-bonding propensity of Trp265 has not been recognized9424344. Notably, KCNQ activators with marked structural diversity appear to act through Trp265 (several examples are shown in Fig. 8), and these share the common feature of a carbonyl oxygen that we suggest acts as an essential hydrogen bond acceptor. Supporting this notion, our findings illustrate that ML-213 is an effective KCNQ3 activator, correlated with its strong surface potential relative to other drugs tested. In the context of understanding drug interactions with ion channels and other receptors, these observations illustrate the importance of investigating specific chemical forces that enable drug interactions with aromatic side chains known to contribute to binding sites in other ion channels (for example, voltage-gated Na+ channels, human ether-a-go-go related gene product (hERG))454647. These insights could guide rational ‘tuning' of the properties of certain functional groups to alter drug properties in desirable ways.


Atomic basis for therapeutic activation of neuronal potassium channels.

Kim RY, Yau MC, Galpin JD, Seebohm G, Ahern CA, Pless SA, Kurata HT - Nat Commun (2015)

Diverse structures of KCNQ openers.Multiple structures of KCNQ channel openers are presented to highlight the overall features of an amide group flanked by various ring structures. Our findings highlight the importance of the amide carbonyl for interaction with KCNQ3 Trp 265 and likely equivalent positions in KCNQ2, 4 and 5. Drugs depicted are (a) retigabine, (b) ztz-240 (described in ref. 24), (c) acrylamide (s)-1, (d) BMS-204352 and (e) an unnamed experimental drug described in ref. 43.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4561856&req=5

f8: Diverse structures of KCNQ openers.Multiple structures of KCNQ channel openers are presented to highlight the overall features of an amide group flanked by various ring structures. Our findings highlight the importance of the amide carbonyl for interaction with KCNQ3 Trp 265 and likely equivalent positions in KCNQ2, 4 and 5. Drugs depicted are (a) retigabine, (b) ztz-240 (described in ref. 24), (c) acrylamide (s)-1, (d) BMS-204352 and (e) an unnamed experimental drug described in ref. 43.
Mentions: By demonstrating the effects of H-bond strength on a range of KCNQ3 activators, our findings suggest the importance of a carbonyl oxygen (usually in a carbamate or amide moiety) for the formation of a negative electrostatic surface potential to act as a H-bond acceptor. Previous screens of compound libraries have investigated important physicochemical features important for drug activity on KCNQ2–5 channels. Several studies have reported the importance of an amide bond (or a carbonyl oxygen) as an essential element of the pharmacophore, although the relationship between this functional group and the H-bonding propensity of Trp265 has not been recognized9424344. Notably, KCNQ activators with marked structural diversity appear to act through Trp265 (several examples are shown in Fig. 8), and these share the common feature of a carbonyl oxygen that we suggest acts as an essential hydrogen bond acceptor. Supporting this notion, our findings illustrate that ML-213 is an effective KCNQ3 activator, correlated with its strong surface potential relative to other drugs tested. In the context of understanding drug interactions with ion channels and other receptors, these observations illustrate the importance of investigating specific chemical forces that enable drug interactions with aromatic side chains known to contribute to binding sites in other ion channels (for example, voltage-gated Na+ channels, human ether-a-go-go related gene product (hERG))454647. These insights could guide rational ‘tuning' of the properties of certain functional groups to alter drug properties in desirable ways.

Bottom Line: Introduction of a non-natural isosteric H-bond-deficient Trp analogue abolishes channel potentiation, indicating that retigabine effects rely strongly on formation of a H-bond with the conserved pore Trp.In addition, potency of numerous retigabine analogues correlates with the negative electrostatic surface potential of a carbonyl/carbamate oxygen atom present in most KCNQ activators.These findings functionally pinpoint an atomic-scale interaction essential for effects of retigabine and provide stringent constraints that may guide rational improvement of the emerging drug class of KCNQ channel activators.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, 2176 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3.

ABSTRACT
Retigabine is a recently approved anticonvulsant that acts by potentiating neuronal M-current generated by KCNQ2-5 channels, interacting with a conserved Trp residue in the channel pore domain. Using unnatural amino-acid mutagenesis, we subtly altered the properties of this Trp to reveal specific chemical interactions required for retigabine action. Introduction of a non-natural isosteric H-bond-deficient Trp analogue abolishes channel potentiation, indicating that retigabine effects rely strongly on formation of a H-bond with the conserved pore Trp. Supporting this model, substitution with fluorinated Trp analogues, with increased H-bonding propensity, strengthens retigabine potency. In addition, potency of numerous retigabine analogues correlates with the negative electrostatic surface potential of a carbonyl/carbamate oxygen atom present in most KCNQ activators. These findings functionally pinpoint an atomic-scale interaction essential for effects of retigabine and provide stringent constraints that may guide rational improvement of the emerging drug class of KCNQ channel activators.

No MeSH data available.