Structural insights into the atomistic mechanisms of action of small molecule inhibitors targeting the KCa3.1 channel pore

Hai M. Nguyen, Vikrant Singh, Brandon Pressly, David Paul Jenkins, Heike Wulff, Vladimir Yarov-Yarovoy

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

The intermediate-conductance Ca2+ -activated K+ channel (KCa3.1) constitutes an attractive pharmacological target for immunosuppression, fibroproliferative disorders, atherosclerosis, and stroke. However, there currently is no available crystal structure of this medically relevant channel that could be used for structure-assisted drug design. Using the Rosetta molecular modeling suite we generated a molecular model of the KCa3.1 pore and tested the model by first confirming previously mapped binding sites and visualizing the mechanism of TRAM- 34 (1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole), senicapoc (2,2-bis-(4-fluorophenyl)-2-phenylacetamide), and NS6180 (4-[[3- (trifluoromethyl)phenyl]methyl]-2H-1,4-benzothiazin-3(4H)-one) inhibition at the atomistic level. All three compounds block ion conduction directly by fully or partially occupying the site that would normally be occupied by K+ before it enters the selectivity filter. We then challenged the model to predict the receptor sites andmechanismsof action of the dihydropyridine nifedipine and an isosteric 4-phenyl-pyran. Rosetta predicted receptor sites for nifedipine in the fenestration region and for the 4-phenyl-pyran in the pore lumen, which could both be confirmed by site-directed mutagenesis and electrophysiology. While nifedipine is thus not a pore blocker and might be stabilizing the channel in a nonconducting conformation or interfere with gating, the 4-phenylpyran was found to be a classical pore blocker that directly inhibits ion conduction similar to the triarylmethanes TRAM-34 and senicapoc. The Rosetta KCa3.1 pore model explains the mechanism of action of several KCa3.1 blockers at the molecular level and could be used for structure-assisted drug design.

Original languageEnglish (US)
Pages (from-to)392-402
Number of pages11
JournalMolecular Pharmacology
Volume91
Issue number4
DOIs
StatePublished - Apr 1 2017

Fingerprint

Nifedipine
Pyrans
Drug Design
Ions
Calcium-Activated Potassium Channels
Molecular Models
Electrophysiology
Site-Directed Mutagenesis
Immunosuppression
Atherosclerosis
Stroke
Binding Sites
Pharmacology
TRAM 34
senicapoc
4-((3-(trifluoromethyl)phenyl)methyl)-2H-1,4-benzothiazin-3(4H)-one

ASJC Scopus subject areas

  • Medicine(all)
  • Molecular Medicine
  • Pharmacology

Cite this

Structural insights into the atomistic mechanisms of action of small molecule inhibitors targeting the KCa3.1 channel pore. / Nguyen, Hai M.; Singh, Vikrant; Pressly, Brandon; Jenkins, David Paul; Wulff, Heike; Yarov-Yarovoy, Vladimir.

In: Molecular Pharmacology, Vol. 91, No. 4, 01.04.2017, p. 392-402.

Research output: Contribution to journalArticle

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