A fluorine scan of non-peptidic inhibitors of neprilysin: Fluorophobic and fluorophilic regions in an enzyme active site

Morgenthaler, Martin; Aebi, Johannes D.; Grüninger, Fiona; Mona, Daniel; Wagner, Björn; Kansy, Manfred; Diederich, François

doi:10.1016/j.jfluchem.2008.02.004

Cited by 23 publications

(15 citation statements)

References 48 publications

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“…These are the feature C  that encodes for the carbon of the carbonyl of the backbone and the carbon of the carbonyl of side chains of asparagine, glutamine, aspartate, and glutamate (i.e., CG of Asn/Asp, and CD of Gln/Glu) and for the carbon atom of the guanidinium group of arginines (CZ Arg). It has been shown,13 that the C‐F moiety points toward the guanidinium moiety of arginines either parallel or orthogonally. In addition, it has also been found that in some cases C‐F can form nonlinear hydrogen bonds with the hydrogen bound to the nitrogen of the guanidinium of arginines 14.…”

Section: Methodsmentioning

confidence: 99%

Combined use of computational chemistry, NMR screening, and X‐ray crystallography for identification and characterization of fluorophilic protein environments

2010

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(19)F NMR screening of fluorinated fragments with different Local Environment of Fluorine, a.k.a. LEF library, is an experimental methodology which, beyond providing useful starting fragments for fragment-based drug discovery projects, offers, in combination with crystal and computational analysis, an approach for the identification of fluorophilic hot-spots in the proteins of interest. The application of this approach in the identification of fluorinated fragments binding to the serine protease trypsin, and the X-ray structures of the complexes are presented. The specific nature of the observed fluorine-protein interactions is discussed and compared with the interactions detected for other fluorinated ligands reported in the protein data bank. The presence of similar 3D arrangements of protein atoms at the fluorine sub-sites is identified with a newly developed tool. In this approach, protein sub-sites are extracted around each fluorine contained in the protein data bank and compared with the query of interest by using a pharmacophoric description.

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Section: Methodsmentioning

confidence: 99%

Combined use of computational chemistry, NMR screening, and X‐ray crystallography for identification and characterization of fluorophilic protein environments

2010

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“…During the simulation the Lennard-Jones, charge, bond and torsions parameters of these additional fluorine sites are turned off. When mutating to a fluorinated system the relevant hydrogen is turned off and fluorine Lennard-Jones and charge parameters are applied to the additional site, this is demonstrated in figure (3). The torsion parameters are mutated from the hydrogenated system to fluorinated system, but the torsions remain on the parent hydrogen and are not transferred to the virtual fluorine.…”

Section: Perturbative Fluorine Scanningmentioning

confidence: 99%

“…Fluorine scanning is a common technique in medicinal chemistry and involves systematic replacement of hydrogen with fluorine. [1][2][3][4][5][6] It can improve binding affinity as well as ADME properties. 7,8 A striking example of the potential is given by the application of fluorine scanning on factor Xa.…”

Section: Introductionmentioning

confidence: 99%

Computational Fluorine Scanning Using Free-Energy Perturbation

Wade

Rizzi

Wang

et al. 2019

J. Chem. Inf. Model.

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We present perturbative fluorine scanning, a computational fluorine scanning approach using free-energy perturbation. This method can be applied to molecular dynamics simulations of a single compound and make predictions for the best binders out of numerous fluorinated analogues. We tested the method on nine test systems: Renin, DPP4, Menin, P38, Factor Xa, CDK2, AKT, JAK2, and Androgen Receptor. The predictions were in excellent agreement with more rigorous alchemical free-energy calculations and in good agreement with experimental data for most of the test systems. However, the agreement with experiment was very poor in some of the test systems and this highlights the need for improved force fields in addition to accurate treatment of tautomeric and protonation states. The method is of particular interest due to the wide use of fluorine in medicinal chemistry to improve binding affinity and ADME properties. The promising results on this test case suggest that perturbative fluorine scanning will be a useful addition to the available arsenal of free-energy methods.

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“…2-Substituted benzimidazoles 61 containing between one and four fluorine atoms were investigated as nonpeptide inhibitors of neprilysin, which is involved in the metabolism of a series of regulatory peptides in the nervous, cardiovascular, and immune systems [33]. The obtained data on the binding capacity of compounds 61 with the receptor confirmed that fluorine with its high negative charge density and low polarizability prefers to direct such a compound into the electropositive regions of the receptor sites.…”

Section: Biological Activitymentioning

confidence: 88%

Fluorine-Containing Benzimidazoles and Their [a]- and [b]Heteroannelated Derivatives: Synthesis and Biological Activity (Review)

Lipunova

Носова

Charushin

2014

Chem Heterocycl Comp

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A fluorine scan of non-peptidic inhibitors of neprilysin: Fluorophobic and fluorophilic regions in an enzyme active site

Cited by 23 publications

References 48 publications

Combined use of computational chemistry, NMR screening, and X‐ray crystallography for identification and characterization of fluorophilic protein environments

Combined use of computational chemistry, NMR screening, and X‐ray crystallography for identification and characterization of fluorophilic protein environments

Computational Fluorine Scanning Using Free-Energy Perturbation

Fluorine-Containing Benzimidazoles and Their [a]- and [b]Heteroannelated Derivatives: Synthesis and Biological Activity (Review)

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