Interaction of d-Tubocurarine with Potassium Channels: Molecular Modeling and Ligand Binding

Rossokhin, Alexey V.; Teodorescu, G.; Grissmer, Stephan; Zhorov, Boris S.

doi:10.1124/mol.105.017970

Cited by 21 publications

(13 citation statements)

References 45 publications

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“…The 9 Å-wide pore of Kv1.2 is consistent with the correolide dimensions predicted to be 9 – 10 Å [19]. A recent study shows that another semirigid bulky ligand, d-tubocurarine binds in the open pore of Kv1.3 [20]. Mapping of the correolide receptor in the Kv1.2-based model of Kv1.3 is now warranted to rationalize mutational studies [15] and provide information for possible design of simpler drugs targeting Kv1.3 channels.…”

Section: Introductionsupporting

confidence: 73%

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Bruhova

Zhorov

2007

BMC Struct Biol

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BackgroundCorreolide, a nortriterpene isolated from the Costa Rican tree Spachea correa, is a novel immunosuppressant, which blocks Kv1.3 channels in human T lymphocytes. Earlier mutational studies suggest that correolide binds in the channel pore. Correolide has several nucleophilic groups, but the pore-lining helices in Kv1.3 are predominantly hydrophobic raising questions about the nature of correolide-channel interactions.ResultsWe employed the method of Monte Carlo (MC) with energy minimization to search for optimal complexes of correolide in Kv1.2-based models of the open Kv1.3 with potassium binding sites 2/4 or 1/3/5 loaded with K+ ions. The energy was MC-minimized from many randomly generated starting positions and orientations of the ligand. In all the predicted low-energy complexes, oxygen atoms of correolide chelate a K+ ion. Correolide-sensing residues known from mutational analysis along with the ligand-bound K+ ion provide major contributions to the ligand-binding energy. Deficiency of K+ ions in the selectivity filter of C-type inactivated Kv1.3 would stabilize K+-bound correolide in the inner pore.ConclusionOur study explains the paradox that cationic and nucleophilic ligands bind to the same region in the inner pore of K+ channels and suggests that a K+ ion is an important determinant of the correolide receptor and possibly receptors of other nucleophilic blockers of the inner pore of K+ channels.

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Section: Introductionsupporting

confidence: 73%

“…Homology model of the pore domain of Kv1.3 that incorporate the outer helices, P-loops, and the inner helices (Table 1) were built using methodology described elsewhere [20]. The X-ray structure of Kv1.2 (Protein Data Bank code 2A79) was used as the template.…”

Section: Methodsmentioning

confidence: 99%

Untitled

Bruhova

Zhorov

2007

BMC Struct Biol

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“…The K + channel blocker amantadine is toxic to P. falciparum [133]. In addition, bicuculline and tubocurarine, which block some K + channels in addition to other targets [134], [135] are also toxic to P. falciparum [37]. Functional evidence will be required before any causal links between inhibition of parasite K + channel activity and anti-parasitic effects can be established.…”

Section: Discussionmentioning

confidence: 99%

Identification of Putative Potassium Channel Homologues in Pathogenic Protozoa

Prole

Marrion

2012

PLoS ONE

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K+ channels play a vital homeostatic role in cells and abnormal activity of these channels can dramatically alter cell function and survival, suggesting that they might be attractive drug targets in pathogenic organisms. Pathogenic protozoa lead to diseases such as malaria, leishmaniasis, trypanosomiasis and dysentery that are responsible for millions of deaths each year worldwide. The genomes of many protozoan parasites have recently been sequenced, allowing rational design of targeted therapies. We analyzed the genomes of pathogenic protozoa and show the existence within them of genes encoding putative homologues of K+ channels. These protozoan K+ channel homologues represent novel targets for anti-parasitic drugs. Differences in the sequences and diversity of human and parasite proteins may allow pathogen-specific targeting of these K+ channel homologues.

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“…Binding of several classical K V channel inhibitors that were originally described to block the Shaker type channel in the early 1980s, such as tetraethylammonium, d ‐tubocurarine, and verapamil, has been studied in K V 1.3 models. These compounds are organic cations and they can block the open K + channels by physically occluding the inner pore and inserting their ammonium group into the ion permeation pathway 93,94 . Binding sites of more potent and selective K V 1.3 small molecule inhibitors are described in the later sections.…”

Section: Kv13 Channel As a Drug Targetmentioning

confidence: 99%

Discovery of K_V1.3 ion channel inhibitors: Medicinal chemistry approaches and challenges

Gubič

Hendrickx

Sterle

et al. 2021

Medicinal Research Reviews

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The K V 1.3 voltage‐gated potassium ion channel is involved in many physiological processes both at the plasma membrane and in the mitochondria, chiefly in the immune and nervous systems. Therapeutic targeting K V 1.3 with specific peptides and small molecule inhibitors shows great potential for treating cancers and autoimmune diseases, such as multiple sclerosis, type I diabetes mellitus, psoriasis, contact dermatitis, rheumatoid arthritis, and myasthenia gravis. However, no K V 1.3‐targeted compounds have been approved for therapeutic use to date. This review focuses on the presentation of approaches for discovering new K V 1.3 peptide and small‐molecule inhibitors, and strategies to improve the selectivity of active compounds toward K V 1.3. Selectivity of dalatazide (ShK‐186), a synthetic derivate of the sea anemone toxin ShK, was achieved by chemical modification and has successfully reached clinical trials as a potential therapeutic for treating autoimmune diseases. Other peptides and small‐molecule inhibitors are critically evaluated for their lead‐like characteristics and potential for progression into clinical development. Some small‐molecule inhibitors with well‐defined structure–activity relationships have been optimized for selective delivery to mitochondria, and these offer therapeutic potential for the treatment of cancers. This overview of K V 1.3 inhibitors and methodologies is designed to provide a good starting point for drug discovery to identify novel effective K V 1.3 modulators against this target in the future.

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Interaction of d-Tubocurarine with Potassium Channels: Molecular Modeling and Ligand Binding

Abstract: Potassium channels play fundamental roles in physiology. Chemically diverse drugs bind in the pore region of K ϩ channels. Here, we homology-modeled voltage-and Ca 2ϩ -gated K

Cited by 21 publications

References 45 publications

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Identification of Putative Potassium Channel Homologues in Pathogenic Protozoa

Discovery of K_V1.3 ion channel inhibitors: Medicinal chemistry approaches and challenges

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Interaction of d-Tubocurarine with Potassium Channels: Molecular Modeling and Ligand Binding

Abstract: Potassium channels play fundamental roles in physiology. Chemically diverse drugs bind in the pore region of K ϩ channels. Here, we homology-modeled voltage-and Ca 2ϩ -gated K

Cited by 21 publications

References 45 publications

Untitled

Untitled

Identification of Putative Potassium Channel Homologues in Pathogenic Protozoa

Discovery of KV1.3 ion channel inhibitors: Medicinal chemistry approaches and challenges

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Discovery of K_V1.3 ion channel inhibitors: Medicinal chemistry approaches and challenges