The Trifluoromethyl Group in Medical Chemistry

Yale, Harry L.

doi:10.1021/jm50003a001

Cited by 182 publications

(92 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5C). These interactions are consistent with the lipophilic properties of group CF 3 (41). Residues M p47 , T p48 , T p49 , V i15 , and I i18 , which are common between Kv1.2 and Kv2.1, also stabilize FLEC binding.…”

Section: Block Of Kv21 Currents By Flec-supporting

confidence: 78%

Overlapping Binding Sites of Structurally Different Antiarrhythmics Flecainide and Propafenone in the Subunit Interface of Potassium Channel Kv2.1*

Madeja

Steffen

Mesic

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Kv2.1 channels, which are expressed in brain, heart, pancreas, and other organs and tissues, are important targets for drug design. Flecainide and propafenone are known to block Kv2.1 channels more potently than other Kv channels. Here, we sought to explore structural determinants of this selectivity. We demonstrated that flecainide reduced the K ؉ currents through Kv2.1 channels expressed in Xenopus laevis oocytes in a voltageand time-dependent manner. By systematically exchanging various segments of Kv2.1 with those from Kv1.2, we determined flecainide-sensing residues in the P-helix and inner helix S6. These residues are not exposed to the inner pore, a conventional binding region of open channel blockers. The flecainide-sensing residues also contribute to propafenone binding, suggesting overlapping receptors for the drugs. Indeed, propafenone and flecainide compete for binding in Kv2.1. We further used Monte Carlo-energy minimizations to map the receptors of the drugs. Flecainide docking in the Kv1.2-based homology model of Kv2.1 predicts the ligand ammonium group in the central cavity and the benzamide moiety in a niche between S6 and the P-helix. Propafenone also binds in the niche. Its carbonyl group accepts an H-bond from the P-helix, the amino group donates an H-bond to the P-loop turn, whereas the propyl group protrudes in the pore and blocks the access to the selectivity filter. Thus, besides the binding region in the central cavity, certain K ؉ channel ligands can expand in the subunit interface whose residues are less conserved between K ؉ channels and hence may be targets for design of highly desirable subtype-specific K ؉ channel drugs.Potassium channels are crucial in physiology. Medically important drugs block the open pore, which is formed by four subunits. Each subunit consists of transmembrane ␣-helical segments S1-S6 and the membrane re-entering extracellular P-loop. The pore-forming domain is composed of four S5-P-S6

show abstract

Section: Block Of Kv21 Currents By Flec-supporting

confidence: 78%

Overlapping Binding Sites of Structurally Different Antiarrhythmics Flecainide and Propafenone in the Subunit Interface of Potassium Channel Kv2.1*

Madeja

Steffen

Mesic

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…The value of CF 3 in medicinal chemistry was recognized long ago as a tool for rigidifying compounds and helping them cross the blood–brain barrier Given the pharmacological significance of fluorinated ligands in protein binding and interaction; and the growing use of CF 3 moieties in drug discovery efforts, future studies examining the interaction of the drug Perazine (TFP‐analog lacking CF 3 ) will help to uncover the role of the CF 3 group in CaM recognition of TFP.…”

Section: Resultsmentioning

confidence: 99%

Opposing orientations of the anti-psychotic drug trifluoperazine selected by alternate conformations of M144 in calmodulin

et al. 2015

View full text Add to dashboard Cite

The anti-psychotic drug trifluoperazine (TFP) is an antagonist observed to bind to calcium-saturated calmodulin ((Ca2+)4-CaM) at ratios of 1:1 (1CTR), 2:1 (1A29), and 4:1 (1LIN). Each structure contains one TFP bound in the hydrophobic cleft of the C-domain of CaM. However, the orientation of the trifluoromethyl (CF3) moiety differs among them: it is buried in the C-domain cleft of 1A29 and 1LIN, but protrudes from 1CTR. We report a 2.0 Å resolution crystallographic structure (4RJD) of TFP bound to the (Ca2+)-saturated C-domain of CaM (CaMC). The asymmetric unit contains two molecules of (Ca2+)2-CaMC. Chain backbones were nearly identical, but the orientation of TFP in the cleft of chain A matched 1A29/1LIN, while TFP bound to chain B matched 1CTR. This was accommodated by a flip of the M144 sidechain and small changes in sidechains of M109 and M145. Docking simulations suggested that the rotamer conformation of M144 determined the orientation of TFP within the cleft of (Ca2+)2-CaMC. Chains A and B show that the open cleft of (Ca2+)2-CaMC is promiscuous in accepting TFP in reversed directions under the same crystallization conditions. Observing multiple orientations of an antagonist bound to a single protein highlights the challenge of designing highly specific pharmaceuticals, and may have importance for QSAR of other CF3-containing drugs such as fluoxetine (anti-depressant) or efavirenz (reverse transcriptase inhibitor). This study emphasizes that a single structure of a complex represents an energetically accessible state, but does not necessarily show the full range of energetically equivalent states.

show abstract

“…Classical organic chemistry has seen a surge in the development of novel trifluoromethylation strategies and protocols [29–35], owed to the high relevance of the trifluoromethyl motif [36, 37]. However, translation of these most useful and often robust and versatile protocols into radiochemistry is not without difficulties.…”

Section: Introductionmentioning

confidence: 99%

Radiosynthesis of [¹⁸F]Trifluoroalkyl Groups: Scope and Limitations

Lien

Riss

2014

BioMed Research International

View full text Add to dashboard Cite

show abstract

The Trifluoromethyl Group in Medical Chemistry

Cited by 182 publications

References 12 publications

Overlapping Binding Sites of Structurally Different Antiarrhythmics Flecainide and Propafenone in the Subunit Interface of Potassium Channel Kv2.1*

Overlapping Binding Sites of Structurally Different Antiarrhythmics Flecainide and Propafenone in the Subunit Interface of Potassium Channel Kv2.1*

Opposing orientations of the anti-psychotic drug trifluoperazine selected by alternate conformations of M144 in calmodulin

Radiosynthesis of [¹⁸F]Trifluoroalkyl Groups: Scope and Limitations

Contact Info

Product

Resources

About

The Trifluoromethyl Group in Medical Chemistry

Cited by 182 publications

References 12 publications

Overlapping Binding Sites of Structurally Different Antiarrhythmics Flecainide and Propafenone in the Subunit Interface of Potassium Channel Kv2.1*

Overlapping Binding Sites of Structurally Different Antiarrhythmics Flecainide and Propafenone in the Subunit Interface of Potassium Channel Kv2.1*

Opposing orientations of the anti-psychotic drug trifluoperazine selected by alternate conformations of M144 in calmodulin

Radiosynthesis of [18F]Trifluoroalkyl Groups: Scope and Limitations

Contact Info

Product

Resources

About

Radiosynthesis of [¹⁸F]Trifluoroalkyl Groups: Scope and Limitations