Systematische Untersuchung von Halogenbrücken in Protein‐Ligand‐ Wechselwirkungen

Hardegger, Leo A.; Kuhn, Bernd; Spinnler, Beat; Anselm, Lilli; Ecabert, Robert; Stihle, M.; Gsell, Bernard; Thoma, Ralf; Diez, Joachim; Benz, Jörg; Plancher, Jean‐Marc; Hartmann, Guido; Banner, David W.; Haap, Wolfgang; Diederich, François

doi:10.1002/ange.201006781

Cited by 91 publications

(57 citation statements)

References 29 publications

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“…These intermolecular distances are in very good agreement with quantum mechanically calculated minimum energy separations (3.0-3.1 ) in our model systems (N-methylacetamide interacting with halogen-substituted phenyl in an X-ray structure-constrained arrangement). [6] The predicted gain in interaction energy by approximately 1 kcal mol À1 from Cl to Br to I, each, correlates qualitatively with the observed increase in binding affinity (Table 1). In sharp contrast, the F atom in (À)-1 bound to hcatL is located at an F···O distance of 4.5 , indicative of an unfavorable interaction when organofluorine points at the O atom of a C=O group.…”

Section: Resultssupporting

confidence: 68%

“…The overlay of the six co-crystal structures of compounds (À)-1 and (À)-3 to (+)-7 ( Figure S4 in the Supporting Information) reveals the previously discussed [6] spring-like mechanism induced by the pyrrolidine pucker, which allows different penetrations of the halogen-bearing aromatic moiety into the S3 pocket. A planar pyrrolidine ring generally allows for a deeper penetration into the S3 pocket than a more puckered one, folding slightly away from the S3 pocket.…”

Section: Resultsmentioning

confidence: 93%

“…[6] The inhibitors are covalently bound through nucleophilic attack of Cys25 on the nitrile in the S1 pocket, with Gln19 in the oxyanion hole of the protease stabilizing the resulting thioimidate anion. Apart from the oxyanion hole interactions, the ligands form hydrogen bonds to Gly68 and Asp162 (green dashed lines in Table 1), and fill the mostly hydrophobic S2 and the more hydrophilic S3 pockets.…”

Section: Resultsmentioning

confidence: 99%

“…Here, we report the increase in biological affinities of two classes of small-molecule inhibitors bound to hcatL [6] and MEK1, [7,8] upon changing the para substituent X on an aryl moiety (ArX) from F, to H, Cl, Br, and I. We provide X-ray crystallographic evidence that XB to a backbone C=O acceptor of the proteins is at the origin of this increase in affinity, by reporting new, highly resolved co-crystal structures of hcatL bound to ligands with X = Cl, Br, and I.…”

Section: Introductionmentioning

confidence: 95%

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Halogen Bonding at the Active Sites of Human Cathepsin L and MEK1 Kinase: Efficient Interactions in Different Environments

et al. 2011

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In two series of small-molecule ligands, one inhibiting human cathepsin L (hcatL) and the other MEK1 kinase, biological affinities were found to strongly increase when an aryl ring of the inhibitors is substituted with the larger halogens Cl, Br, and I, but to decrease upon F substitution. X-ray co-crystal structure analyses revealed that the higher halides engage in halogen bonding (XB) with a backbone C=O in the S3 pocket of hcatL and in a back pocket of MEK1. While the S3 pocket is located at the surface of the enzyme, which provides a polar environment, the back pocket in MEK1 is deeply buried in the protein and is of pronounced apolar character. This study analyzes environmental effects on XB in protein-ligand complexes. It is hypothesized that energetic gains by XB are predominantly not due to water replacements but originate from direct interactions between the XB donor (Caryl-X) and the XB acceptor (C=O) in the correct geometry. New X-ray co-crystal structures in the same crystal form (space group P2(1)2(1)2(1)) were obtained for aryl chloride, bromide, and iodide ligands bound to hcatL. These high-resolution structures reveal that the backbone C=O group of Gly61 in most hcatL co-crystal structures maintains water solvation while engaging in XB. An aryl-CF3-substituted ligand of hcatL with an unexpectedly high affinity was found to adopt the same binding geometry as the aryl halides, with the CF3 group pointing to the C=O group of Gly61 in the S3 pocket. In this case, a repulsive F2C-F⋅⋅⋅O=C contact apparently is energetically overcompensated by other favorable protein-ligand contacts established by the CF3 group.

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Section: Resultssupporting

confidence: 68%

Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

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Halogen Bonding at the Active Sites of Human Cathepsin L and MEK1 Kinase: Efficient Interactions in Different Environments

et al. 2011

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“…A modulation of the X-bond in protein-inhibitor complexes was used to reduce the IC 50 values accordingly. [13,14] Reference interaction energies (DE) for the X-bond are obtained using the highly accurate CCSD(T) calculations. Hartree-Fock (HF) and density funtional theory (DFT) usually give too low DE values.…”

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confidence: 99%

The Dominant Role of Chalcogen Bonding in the Crystal Packing of 2D/3D Aromatics

et al. 2014

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Abstract:The chalcogen bond is a nonclassical s-hole-based noncovalent interaction with emerging applications in medicinal chemistry and material science. It is found in organic compounds, including 2D aromatics, but has so far never been observed in 3D aromatic inorganic boron hydrides. Thiaboranes, harboring a sulfur heteroatom in the icosahedral cage, are candidates for the formation of chalcogen bonds. The phenylsubstituted thiaborane, synthesized and crystalized in this study, forms sulfur···p type chalcogen bonds. Quantum chemical analysis revealed that these interactions are considerably stronger than both in their organic counterparts and in the known halogen bond. The reason is the existence of a highly positive s-hole on the positively charged sulfur atom. This discovery expands the possibilities of applying substituted boron clusters in crystal engineering and drug design.

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Halogenbrücken‐induzierte Aktivierung einer Kohlenstoff‐ Heteroatom‐Bindung

et al. 2011

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Professor Robert Weiss zum 70. Geburtstag gewidmetHalogenbrücken sind attraktive nichtkovalente Wechselwirkungen zwischen terminalen Halogenatomen in Verbindungen des allgemeinen Typs R-X (X = Cl, Br, I) und LewisBasen (LBs). [1][2][3] Voraussetzung für die Bildung einer starken Halogenbrücke ist ein möglichst elektronegatives Fragment R, beispielsweise in Form polyfluorierter Alkyl-oder Phenylreste (Schema 1). [1,2] Dadurch wird einerseits eine Region positiven elektrostatischen Potentials an der von R abgewandten Seite des Halogenatoms induziert ("s-Loch") [4] und andererseits der n!s*-Ladungstransfer der Lewis-Base mit dem Halogenbrückendonor R-X begünstigt.[5] Die elektronische Natur der Wechselwirkung bedingt bei Halogenbrü-cken einen R-X···LB-Winkel von ca. 1808 und somit eine hohe Direktionalität. [2a,b] Obwohl schon lange bekannt und nachgewiesen, [5a,b] haben Halogenbrücken erst seit den 1990er Jahren verstärk-tes Interesse erfahren. [2a,b, 6] Neben grundlegenden Arbeiten wurden bisher vor allem Untersuchungen zum rationalen Design von Festkörpern veröffentlicht, [2b,c, 7] etwa für Flüs-sigkristalle [8] und leitfähige Materialien.[9] Starke Halogenbrücken (XBs) wurden hierbei oftmals mit Halogeniden als Lewis-Basen beobachtet. [2a, 10] Auch in Lösung gab es schon früh Hinweise [11] (und inzwischen auch Nachweise) [3c, 12] für das Auftreten von XBs. Erste Anwendungen in Form von XBbasierten Halogenidrezeptoren wurden aber erst kürzlich vorgestellt.[13] Bolm et al. berichteten zudem über die katalytische Wirkung von XB-Donoren des Typs 1 (Schema 1) bei der Reduktion von Chinolinderivaten. [14] Die Eigenschaft von Thioharnstoffderivaten, [15] als Rezeptoren für Anionen fungieren zu können, wurde in letzter Zeit zunehmend zur Aktivierung von Substraten und zur asymmetrischen Induktion in Wasserstoffbrücken-basierten organokatalytischen Reaktionen eingesetzt. [16,17] Dabei bindet der Katalysator an (meist während der Reaktion freigesetzte) Halogenide, [17b,d] Angesichts der zahlreichen Beispiele von Halogenbrü-ckenaddukten mit Halogenidsalzen hatten wir uns zum Ziel gesetzt, Kohlenstoff-Halogen-Bindungen mit starken XBDonoren zu aktivieren. Deren Koordination an die freien Elektronenpaare des terminalen Halogenatoms sollte zumindest eine Lockerung der entsprechenden C-X-Bindung, wenn nicht im Extremfall sogar eine heterolytische Spaltung bewirken können. Zusätzliche Triebkraft für die Gesamtreaktion (beispielsweise die Substitution des Halogenids durch ein zugesetztes Nucleophil) könnte aus der Unlöslichkeit des gebildeteten XB-Addukts aus XB-Donor und Halogenidsalz resultieren. Im weitesten Sinne würde der XB-Donor somit als organisches Ag + -¾quivalent fungieren. Als ideales Testsubstrat zur Verwirklichung dieser Idee erschien uns Benzhydrylbromid [20] (4; Tabelle 1), dessen vergleichsweise labile C-Br-Bindung beispielsweise von Ag + -Salzen aktiviert werden kann.[21] Deuteriertes Acetonitril als Solvens sollte einerseits gute Lösungseigenschaften gewähr-leisten und zudem die Bildung von XB-Add...

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Systematische Untersuchung von Halogenbrücken in Protein‐Ligand‐ Wechselwirkungen

Cited by 91 publications

References 29 publications

Halogen Bonding at the Active Sites of Human Cathepsin L and MEK1 Kinase: Efficient Interactions in Different Environments

Halogen Bonding at the Active Sites of Human Cathepsin L and MEK1 Kinase: Efficient Interactions in Different Environments

The Dominant Role of Chalcogen Bonding in the Crystal Packing of 2D/3D Aromatics

Halogenbrücken‐induzierte Aktivierung einer Kohlenstoff‐ Heteroatom‐Bindung

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