A Fluorine Scan of Thrombin Inhibitors to Map the Fluorophilicity/Fluorophobicity of an Enzyme Active Site: Evidence for CF⋅⋅⋅CO Interactions

Olsen, Jacob; Banner, David W.; Seiler, Paul; Sander, Ulrike Obst; D’Arcy, Allan; Stihle, M.; Müller, Klaus; Diederich, François

doi:10.1002/anie.200351268

Cited by 189 publications

(122 citation statements)

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“…[5] Apparently, the role of fluorine in molecular recognition strongly depends on the surrounding molecular environment. Similar effects have been observed in the fields of medicinal chemistry and protein design, in which the fluorophilicity/fluorophobicity of the protein environment affects the affinity of fluorine-substituted ligands [7][8][9] or the stabilizing influence of fluorine-containing artificial amino acids. [10,11] With the goal of addressing the influence of the environment on the molecular recognition thermodynamics of organic fluorine, we have undertaken a combined experimental/computational study of fluoA C H T U N G T R E N N U N G robenzene self-pairing in the context of duplex RNA.…”

mentioning

confidence: 54%

“…[47][48][49][50] Attractive H···F dipolar interactions have been described, however, for well-structured molecular environments in which heteroatom acceptors are excluded, such as the thrombin active site [7,8] or engineered crystals. [42,51] Apparently, the fluorobenzene self-pairs in the context of duplex RNA constitute a well-structured supramolecular system, which leads to favorable interactions between selfpairs of 3 and 4.…”

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confidence: 97%

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Determinants of the Unexpected Stability of RNA Fluorobenzene Self Pairs

et al. 2008

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confidence: 54%

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confidence: 97%

Determinants of the Unexpected Stability of RNA Fluorobenzene Self Pairs

et al. 2008

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“…7) to identify fluorophilic and fluorophobic environments in the thrombin active site [65,66]. For the highest affinity inhibitor (9), the authors identified C-F•••H-C-C=O and C-F•••C=O contacts of the 4-fluorophenyl groups with Asn 98.…”

Section: Interactions Of the C-f Dipolementioning

confidence: 98%

The Strength of Weak Interactions: Aromatic Fluorine in Drug Design

DiMagno

Sun

2006

CTMC

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Selective aromatic fluorine substitution can increase the affinity of a molecule for a macromolecular recognition site through non-covalent interactions. These effects are evaluated most accurately by direct comparison of binding affinities of selectively fluorinated compounds with their corresponding hydrocarbons. In cases where structural data confirm similar binding geometries for the fluorocarbon and hydrocarbon analogues, reliable estimates for the impact of fluorination upon arene-pi...X and C-F...X interaction energies are possible. Existing studies show that fluorination's impact on any individual molecular interaction is quite modest. Upon binding to a protein receptor, cumulative fluorinated aromatic quadrupolar and C-F...X dipolar interaction energies rarely differ from those the corresponding hydrocarbons by more than 1.3 kcal/mol, and most individual interactions appear to be in the 0.1-0.4 kcal/mol range. Similarly, non-ideal selective fluorination is rarely associated with a dramatic decrease in affinity, because the impact of weak repulsive interactions in the bound state is counterbalanced by increased lipophilicity.

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“…Therefore it can be argued that these C -F···H -C interactions can be classified as weak hydrogen bonds. The enhanced positive polarisation of the hydrogen atom ortho to the fluorine substituent is thought to enhance the face-to-edge interaction of the inhibitor with Trp 215 in the hydrophobic D pocket but the interaction of fluorine with Asn 98 is largely responsible for the increase in activity seen with the 4-fluorobenzyl derivative [49].…”

Section: Thrombin Inhibitorsmentioning

confidence: 99%

The role of fluorine in medicinal chemistry

Shah

Westwell

2007

Journal of Enzyme Inhibition and Medicinal Chemistry

639

392

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The small and highly electronegative fluorine atom can play a remarkable role in medicinal chemistry. Selective installation of fluorine into a therapeutic or diagnostic small molecule candidate can enhance a number of pharmacokinetic and physicochemical properties such as improved metabolic stability and enhanced membrane permeation. Increased binding affinity of fluorinated drug candidates to target protein has also been documented in a number of cases. A further emerging application of the fluorine atom is the use of 18 F as a radiolabel tracer atom in the exquisitely sensitive technique of Positron Emission Tomography (PET) imaging. This short review aims to bring together these various aspects of the use of fluorine in medicinal chemistry applications, citing selected examples from across a variety of therapeutic and diagnostic settings. The increasingly routine incorporation of fluorine atom(s) into drug candidates suggests a bright future for fluorine in drug discovery and development. A major challenge moving forward will be how and where to install fluorine in a rational sense to best optimise molecular properties.

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A Fluorine Scan of Thrombin Inhibitors to Map the Fluorophilicity/Fluorophobicity of an Enzyme Active Site: Evidence for CF⋅⋅⋅CO Interactions

Cited by 189 publications

References 32 publications

Determinants of the Unexpected Stability of RNA Fluorobenzene Self Pairs

Determinants of the Unexpected Stability of RNA Fluorobenzene Self Pairs

The Strength of Weak Interactions: Aromatic Fluorine in Drug Design

The role of fluorine in medicinal chemistry

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