An Unusual Intramolecular Halogen Bond Guides Conformational Selection

Article abstract of DOI:10.1002/anie.201804917

PIK-75 is a phosphoinositide-3-kinase (PI3K) α-isoform-selective inhibitor with high potency. Although published structure–activity relationship data show the importance of the NO₂ and the Br substituents in PIK-75, none of the published studies could correctly determine the underlying reason for their importance. In this publication, we report the first X-ray crystal structure of PIK-75 in complex with the kinase GSK-3β. The structure shows an unusual U-shaped conformation of PIK-75 within the active site of GSK-3β that is likely stabilized by an atypical intramolecular Br???NO₂ halogen bond. NMR and MD simulations show that this conformation presumably also exists in solution and leads to a binding-competent preorganization of the PIK-75 molecule, thus explaining its high potency. We therefore suggest that the site-specific incorporation of halogen bonds could be generally used to design conformationally restricted bioactive substances with increased potencies.

Full text of DOI:10.1002/anie.201804917

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: An Unusual Intramolecular Halogen Bond guides Conformational
Selection
Authors: Roberta Tesch, Christian Becker, Matthias Philipp Müller,
Michael Edmund Beck, Lena Quambusch, Matthäus Getlik,
Jonas Lategahn, Niklas Uhlenbrock, Fanny Nascimento
Costa, Marcelo D. Polêto, Pedro de Sena Murteira Pinheiro,
Daniel Alencar Rodrigues, Carlos Mauricio Sant’Anna, Fabio
Furlan Ferreira, Hugo Verli, Carlos Alberto Manssour Fraga,
and Daniel Rauh
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201804917
Angew. Chem. 10.1002/ange.201804917
Link to VoR: http://dx.doi.org/10.1002/anie.201804917
http://dx.doi.org/10.1002/ange.201804917

10.1002/anie.201804917
Angewandte Chemie International Edition
COMMUNICATION
An Unusual Intramolecular Halogen Bond guides Conformational
Selection
Roberta Tesch[a,b], Christian Becker[a], Matthias Philipp Müller[a], Michael Edmund Beck[c], Lena
Quambusch[a], Matthäus Getlik[a], Jonas Lategahn[a], Niklas Uhlenbrock[a], Fanny Nascimento Costa[d],
Marcelo D. Polêto[e], Pedro de Sena Murteira Pinheiro[b], Daniel Alencar Rodrigues[b], Carlos Mauricio
R. Sant’Anna[b,f], Fabio Furlan Ferreira[d], Hugo Verli[e], Carlos Alberto Manssour Fraga[b],* and Daniel
Rauh[a],*
Abstract: PIK-75 is a phosphoinositide-3-kinase (PI3K) α-isoform-
selective inhibitor with high potency. Although published SAR data
show the importance of the NO2 and the Br substituents in PIK-75,
none of the published studies could correctly assign the underlying
reason for their importance. In this publication, we report the first X-
ray crystal structure of PIK-75 in complex with the kinase GSK-3β.
The structure shows an unusual U-shaped conformation of PIK-75
within the active site of GSK-3β that is likely stabilized by an atypical
intramolecular Br···NO2 halogen bond. NMR and MD simulations
show that this conformation presumably also exists in solution and
last 20 years. Major efforts undertaken by the pharmaceutical
industry and academic research have led to highly potent
inhibitors that are used in patients and have increased our
understanding of the molecular mechanisms of kinases involved
different diseases.[1] The small molecule PIK-75 (Figure 1) is one
example of a small molecule inhibitor with high potency and
selectivity toward the α-isoform of the catalytic subunit of
phosphoinositide-3-kinases (PI3Ks) and glycogen synthase
kinase-3β (GSK-3β, IC50 = 10 nM)[2], but also inhibits several other
kinases (data from
a kinase profiling are provided in
leads to a binding competent pre-configuration of the PIK-75 molecule, Supplementary Table 1). PI3Ks constitute a family of kinases
thus explaining its high potency. We therefore suggest that the site-
specific incorporation of halogen bonds could be generally used to
design conformationally restricted bioactive substances with
increased potencies.
involved
in
production
of
the
second
messenger
phosphatidylinositol-3,4,5-triphosphate and mutations have been
shown to be important in the development of cancer and other
diseases,[3] thus making available inhibitors attractive targets for
structure-guided improvement of their potency and selectivity.
Several studies have attempted to predict the binding mode
of PIK-75 within the active site of kinases, but they have led to
different conclusions[2c, 4] (and none has correctly predicted the
conformation of PIK-75 within the active site as outlined below).
In this publication, we present the first co-crystal structure of PIK-
75 in complex with GSK-3β, a kinase acting downstream of PI3Ks
that phosphorylates many intracellular targets[3] and has been
studied as a potential target in e.g. type II diabetes and Alzheimer
The selective inhibition of kinases involved in a variety of
signaling cascades has attracted increasing attention within the
[a]
Dr. Roberta Tesch, Dr. Christian Becker, Dr. Matthias P. Müller,
M.Sc. Lena Quambusch, Dr. Matthäus Getlik, Dr. Jonas Lategahn,
M.Sc. Niklas Uhlenbrock, Prof. Daniel Rauh
Faculty of Chemistry and Chemical Biology
TU Dortmund University
[5]
disease. We show that PIK-75 adopts a conformation that is
Otto-Hahn-Strasse 4a, 44227 Dortmund, Germany
E-mail: daniel.rauh@tu-dortmund.de
stabilized by an intramolecular halogen bond of a type that has
not been described before. MD simulations show that this binding-
competent conformation is also present in solution, thus
explaining the high potency of the inhibitor.
[b]
Dr. Roberta Tesch, M.Sc. Pedro de Sena Murteira Pinheiro, M.Sc.
Daniel Alencar Rodrigues, Prof. Carlos Maurício R. Sant’Anna, Prof.
Carlos Alberto Manssour Fraga
Laboratório de Avaliação e Síntese de Substâncias Bioativas
(LASSBio)
Instituto de Ciências Biomédicas, Universidade Federal do Rio de
Janeiro
Av. Carlos Chagas Filho, 373, CEP 21941-902
Rio de Janeiro, Brazil
E-mail: cmfraga@ccsdecania.ufrj.br
In order to gain insight into the structural interplay within the
kinase domain of GSK3, we co-crystallized PIK-75 in complex
with GSK-3β (residues 26–393). A dataset was collected from a
single crystal and the structure solved by molecular replacement
(resolution 2.6 Å, Rwork = 22.2%, Rfree = 25.9%, Supplementary
Table 2). The asymmetric unit consists of two molecules of GSK-
3β, both of which are phosphorylated at Tyr216 and show a very
similar overall conformation (one molecule is shown in Figure 1,
A). Additional electron density observed within the active site
could be clearly and unambiguously modelled with PIK-75. The
correct orientation of PIK-75 (Figure 1, B) was furthermore
verified by the strong anomalous signal resulting from the Br atom
present in the inhibitor (Figure 1, C).
[c]
[d]
Dr. Michael E. Beck
Bayer AG, division Crop Science
Alfred-Nobel-Str. 50, 40789 Monheim am Rhein, Germany
Dr. Fanny N. Costa, Prof. Fabio Furlan Ferreira
Centro de Ciências Naturais e Humanas
Universidade Federal do ABC
São Paulo, Brazil
[d]
[f]
MSc. Marcelo D. Polêto, Prof. Hugo Verli
Centro de Biotecnologia
Universidade Federal do Rio Grande do Sul
Av. Bento Gonçalves, 9500, Porto Alegre, Brazil
Prof. Carlos Maurício R. Sant’Anna,
Departamento de Química, Instituto de Ciências Exatas
Universidade Federal Rural do Rio de Janeiro
Seropédica, Brazil
Supporting information for this article is given via a link at the end of
the document
This article is protected by copyright. All rights reserved.

10.1002/anie.201804917
Angewandte Chemie International Edition
COMMUNICATION
Figure 1. Structure of PIK-75 in complex with the kinase GSK-3β. (A) Overview of GSK-3β (amino acids 26–393, uniprot ID P49841). The hinge region (orange),
glycine-rich loop (blue), αC-helix (red) and the activation loop (green) as well as PIK-75 (yellow) are highlighted. (B) The major interactions of PIK-75 with Phe67
,
Lys85 and Val135 are indicated (the QR-code can be used to visualize the structure in augmented reality[6]). (C) Chemical structure of PIK-75. (D) Stereo view of PIK-
75, the FO-FC simulated annealing omit map (σ = 3.0, green) as well as the anomalous map (σ = 5.0, magenta; diffraction data was collected close to the Br
absorption edge at λ = 0.91883 Å) are shown.
Interactions were observed between one of the PIK-75
imidazo[1,2-a]pyridine nitrogen atoms and the GSK-3β Val135
backbone NH-group (hinge region), similarly to the adenine ring
of ATP and other ATP competitive inhibitors.[7] Additionally, the
NO2 group of PIK-75 interacts with the charged ε-amino group of
the catalytic residue Lys85 and its 2-methyl-5-nitrophenyl group
interacts via π-stacking with the Phe67ring within the glycine-rich
loop (Figure 1, A). Most notable, however, is the unusual U-
shaped conformation of PIK-75 within the active site that was not
predicted by any of the modelling studies performed previously to
predict the binding mode of the inhibitor within the active site of
kinases.[2c, 4] This unusual conformation of PIK-75 allows for the
C-Br bond to point toward the NO2 group plane with an C–Br···N
angle of ~120° and a 3.3 Å distance between the bromine and
nitrogen atoms. This value is less than the sum of their van der
Waals radii (Supplementary Fig. 1), indicating a previously
unknown type of intramolecular halogen bond between the Br and
the NO2 group.
observed in the current study does not fit any of these categories
because of resticted possible relative orientations of the Br and
the NO2 due to the connecting molecular scaffold.
Recently, Zhang and co-workers emphasized the
importance of intramolecular halogen bonds and their role in
stabilizing a particular conformation of a molecule.[9] We thus
speculated that PIK-75 might adopt the same U-shaped
conformation in solution as compared to the conformation
observed within the active site of GSK-3β. To test this hypothesis,
we first determined the crystal structure of PIK-75 by X-ray
powder diffraction[10]. PIK-75 crystallized in a monoclinic (P21/n)
crystal system with Z = 4 and Z’ = 1 (data statistics are shown in
Supplementary Table 3) and indeed adopted a similar U-shaped
conformation (Figure 2 and Supplementary Fig. 1), indicating
that this conformation is also preferred in the absence of the
enzyme. It should be noted, however, that we observed a
difference of ~10° between the angle of the C-Br···NO2 in the
GSK-3β bound and unbound structures (Supplementary Fig. 2
and Supplementary Table 4). The prearrangement of the
inhibitor was additionally validated by two-dimensional NMR
experiments (Figure 2 and Supplementary Fig. 3), and the
observed nuclear correlation between the benzyl moiety and the
pyridine further validates the presence of the U-shaped conformer.
In C-X···NO2 (X = F, Cl, Br, I) intermolecular interactions
previously reported in the literature, the halogen atom is in close
proximity to one or both of the oxygen atoms to give a three-
centered bifurcated system. The type of interaction can be further
characterized as symmetric bifurcated, asymmetric bifurcated or
mono-coordinated.[8] The intramolecular C-Br···NO2 interaction
This article is protected by copyright. All rights reserved.

10.1002/anie.201804917
Angewandte Chemie International Edition
COMMUNICATION
Figure 2. Small molecule crystal structure and 2D-NMR analysis of PIK-75. (A) Relative orientation and distances between the Br and the NO2-group in the
small molecule crystal structure of PIK-75 (top) and overlay of GSK-3β co-crystallized PIK-75 (gray) and the small molecule crystal structure (purple; bottom) (B)
1H-NOESY spectra of PIK-75 observed in DMSO-d6, which elucidates resonances from nuclei that are spatially close, rather than through direct bond connection;
(C) NOESY cross-correlations for PIK-75 (green). The observed spatial interaction A indicates an intramolecular correlation between the benzylic proton at 8.73 ppm
and the pyridine proton at 9.26 ppm, indicating a prearranged conformer of PIK-75.
In order to gain a better understanding of the factors that
contribute to this conformation of PIK-75, we carried out ab initio
post-Hartree-Fock calculations to evaluate existing intramolecular
interactions. In addition, we also used the corresponding des-nitro
analogue to determine the importance of the nitro substituent on
the interaction with the bromine atom. The geometries of both
compounds were fully optimized in gas-phase according to the
second-order Møller-Plesset perturbation theory (MP2) using the
6-31+G* basis set[11], followed by a single point energy calculation
using CAM-B3LYP/6-311G(3d) level of theory.
To study the intramolecular interaction in the orbital
perspective, the analysis of natural bond orbital (NBO) were
focused on the second-order perturbative estimation of donor-
acceptor (bonding-antibonding) interactions. The NBO analysis
resulted in a table with the stabilization energy E(2) value between
each donor-acceptor (bonding-antibonding orbitals) (see Methods
online). No stabilization energy E(2) between the nitro group and
the bromine atom were observed, suggesting that this energy is
above 0.5 kcal·mol-1 (the threshold for printing E(2) in the output
file). This was further verified by fragmentation of PIK-75 into two
small representative parts, i.e. 6-bromoimidazo[1,2-a]pyridine
and 2-hydrosulfonyl-1-methyl-4-nitrobenzene, and re-calculation
of the NBO analysis. The result gave an E(2)= 0.23 kcal·mol-1
between a lone pair of one of the nitro group oxygen atoms and
the C–Br antibonding orbital (nO→σC–Br*). This type of interaction
is characterized by the formation of so called “σ-hole”, first defined
in the literature as the lowest electron density region along a
halogen bond C-X (X= F, Cl, Br, I)[12] that can perform attractive
interaction with electron rich system (such as lone pairs and π
hypothesize that other factors could additionally contribute to the
C-Br···NO2 intramolecular interaction observed here.
The overlay of the imidazo-pyridine core of PIK-75 and its
des-nitro analogue, revealed a difference and a shift of 2.2 Å of
the phenyl-ring (Figure 3, A and Supplementary Table 4). The
electrostatic potential maps around the C-Br bond showed the
formation of the σ-hole in both molecules and using the maximal
and minimal electrostatic potential on a surface map (Vs,max and
Vs,min), the nature of this noncovalent interaction was evaluated.[13]
The Vs, max in the σ-hole region varied by 4.3 kcal·mol-1 between
PIK-75 and the des-nitro analogue, showing that the addition of
the nitro group on PIK-75 changes the charge distribution around
the σ-hole region (Figure 3, B). The electron density along the C-
Br bond, as expected, also differs between PIK-75 and the des-
nitro analogue as indicated by the presence of a more negatively
charged region in the surface map of PIK-75 (VS,min= -13.9
kcal·mol-1 vs. VS,min= -11.0 kcal·mol-1 for the des-nitro analogue)
(Figure 3, C and D). In PIK-75, the region around the nitrogen
atom of the nitro group shows a VS,max= 19.4 kcal·mol-1 and it
points toward the axis of the C-X bond (Figure 3, C). The
electrostatic potential surface map shows that the nitrogen atom
could act as an electrophile interacting with the extension of C-Br
bond, which has negative potential in comparison to the σ-hole,
thus forming a classical dipole-dipole interaction. These findings
are further supported by QTAIM analysis of the electron density,
as the QTAIM graph features a bond critical path connecting
Bromine with the Nitro-function (Supplementary Fig. 6)
system). The weak nO→σC–Br* interaction has led us to
This article is protected by copyright. All rights reserved.

10.1002/anie.201804917
Angewandte Chemie International Edition
COMMUNICATION
Figure 3. Electronic properties of PIK-75 and the des-nitro analogue. (A) Overlay of the ground-state conformations of PIK-75 (gray) and the des-nitro analogue
(cyan). (B) Electrostatic potential maps for PIK-75 (top) and the des-nitro analogue (bottom), highlighting the shape of the σ-hole and the maximal energy values of
the surface for that particular region (VS,max). (C) Cross-section of the electrostatic potential surface of PIK75, highlighting the positive region of the nitro group and
the influence on the σ-hole region of the bromine atom, described in terms of VS,max. (D) Cross-section of the electrostatic potential surface of the des-nitro analogue,
highlighting the stronger σ-hole region of the bromine atom, described in terms of VS,max. Surfaces were calculated in the MP2/6-31+G* level of theory (IsoValue=
0.002).
After identifying that the intramolecular halogen bond in PIK-
75 was also driven by classical electrostatic forces, we
implemented molecular dynamics (MD) simulations for 1 µs in
aqueous solution to investigate the stability of the proposed
interaction of PIK-75. The statistical analysis of the distribution of
torsional angles throughout the simulation revealed only two
conformational populations, with a distribution of 46% and 54%
for the minor and major populations, respectively. The main
difference between these two ensembles is the rotation of the
dihedral angle φ3 (H3C–N–N=CH), with average angles of -10°
(major) and 90° (minor) (Figure 4, A and B). The RMSD values
calculated between each frame of the trajectory against the co-
crystallized conformation of PIK-75 in complex with GSK-3β and
the small molecule crystal structure (Figure 4, C) suggest that
conformations similar to the GSK-3β co-crystallized conformation
exist in solution, indicated by the high frequency of conformations
with an RMSD ≤1.5 Å. Here, the minor conformational ensemble
of PIK-75 is more structurally related to the co-crystallized
conformation than the major ensemble (Supplementary Fig. 4).
The Br···NO2 interaction was also investigated during the
molecular dynamics simulation. Our results revealed an average
Br···NO2 distance of ~4 Å and C–Br···N angle of ~105° for the
minor population, while the major population has an average Br-
NO2 distance of ~6 Å and a C–Br···N angle of ~85°. These results
reinforce the similarity between the minor population and the co-
This article is protected by copyright. All rights reserved.

10.1002/anie.201804917
Angewandte Chemie International Edition
COMMUNICATION
crystallized conformation and suggest that the proper torsions,
angles and distances required for the Br···NO2 interaction are not
only possible, but frequently adopted in aqueous solution.
Figure 4. Molecular dynamics simulations of the conformational space adopted by PIK-75 in solution. (A) Dihedral composition of PIK-75 and relative
abundance throughout molecular dynamics (MD) simulation reveals a bimodal distribution of φ3 (green). (B) The two most prevalent conformational populations with
φ3 = -10º (top) and φ3 = 90 (bottom). (C) RMSD calculations of PIK-75 structural ensemble during MD simulations compared to the conformation of PIK-75 observed
in complex with GSK-3β (grey) and in the small molecule structure of PIK-75 (purple). The similarity, especially to the conformation observed in the co-crystal
structure with GSK-3β, reinforces the idea that PIK-75 adopts a similar conformation also in solution.
Halogen bonding interactions have recently attracted
considerable interest for the development of molecules with
enhanced biological activity.[14] The International Union of Pure
and Applied Chemistry (IUPAC) defines a halogen bond as an
attractive interaction between an electrophilic region associated
with a halogen atom and a nucleophilic region in another, or the
same, molecular entity.[15] Compounds capable of forming
halogen bonds can facilitate the formation of short contacts
This article is protected by copyright. All rights reserved.

10.1002/anie.201804917
Angewandte Chemie International Edition
COMMUNICATION
between the carbonyl and aromatic moieties of backbone amino
acid residues, leading to pronounced changes in the
selectivity,[14a] as well as the conformation of the kinase.[14b] In the
present study, we report a new crystal structure of GSK-3β bound
to the inhibitor PIK-75 that is stabilized by an unusual
intramolecular halogen bond in a binding competent conformation.
In subsequent experiments, we confirm that this conformation is
however not only adopted within the active site of GSK-3β, but
also present in solution, in agreement with previous studies
showing that small molecules frequently adopt the biologically
active conformation even in the absence of the target enzyme.[16]
To date, studies of halogen bonds in small molecule crystals
have mainly focused on analysis of intermolecular interactions
between donor-acceptor compounds[17] leading to the classical
interpretation of the directionality of the halogen bond. However,
it is not surprising that the situation is different in intramolecular
interactions involving halogen bonds (some examples of
intramolecular C-X···NO2 interactions observed in molecules
retrieved from the Cambridge Structural Database CSD are
shown in Supplementary Figure 5). In this study, we observed a
mixed nature of the PIK-75 C-X···NO2 intramolecular halogen
bond interaction, with contributions from the classical σ-hole
Nível Superior (CAPES) and Fundação de Amparo à Pesquisa do
Estado do Rio Grande do Sul (FAPERGS), German Federal
Ministry for Education and Research (NGFNPlus and e:Med)
(Grant No. BMBF 01GS08104, 01ZX1303C) and by the Deutsche
Forschungsgemeinschaft (DFG). DR thanks the German federal
state North Rhine- Westphalia (NRW), European Union
(European Regional Development Fund: Investing In Your
Future) (EFRE-800400).
Keywords: Glycogen synthase kinase-3β • halogen bond •
Molecular dynamics • PIK-75 • X-ray diffraction
[1]
[2]
P. Cohen, D. R. Alessi, ACS chemical biology 2013, 8, 96-104.
aC. Grutter, J. R. Simard, S. C. Mayer-Wrangowski, P. H. Schreier,
J. Perez-Martin, A. Richters, M. Getlik, O. Gutbrod, C. A. Braun, M.
E. Beck, D. Rauh, ACS chemical biology 2012, 7, 1257-1267; bM.
Hayakawa, H. Kaizawa, K. Kawaguchi, N. Ishikawa, T. Koizumi, T.
Ohishi, M. Yamano, M. Okada, M. Ohta, S. Tsukamoto, F. I.
Raynaud, M. D. Waterfield, P. Parker, P. Workman, Bioorgan Med
Chem 2007, 15, 403-412; cZ. H. Zheng, S. I. Amran, P. E.
Thompson, I. G. Jennings, Mol Pharmacol 2011, 80, 657-664.
L. C. Cantley, Science 2002, 296, 1655-1657.
aR. Frederick, W. A. Denny, J Chem Inf Model 2008, 48, 629-638;
bM. Han, J. Z. H. Zhang, Journal of Chemical Information and
Modeling 2010, 50, 136-145; cY. Li, Y. Wang, F. Zhang, J Mol
Model 2010, 16, 1449-1460; dD. A. Sabbah, J. L. Vennerstrom, H.
Z. Zhong, Journal of Chemical Information and Modeling 2010, 50,
1887-1898.
[3]
[4]
interaction (although weak) in addition to
a dipole-dipole
interaction between the nitro group nitrogen atom and the
elongation of the C-Br bond. Although the IUPAC definition of a
halogen bond only accounts for interactions with the σ-hole
region[15], Politzer and co-workers explain the nature of the
halogen bond as Coulombic interactions that involve not only a
direct interaction through the σ-hole, but also an interaction with
the electron dense regions along the C-X bond.[18] Thus, our
finding that the intramolecular halogen bond of PIK-75 is not
driven exclusively by an interaction with the σ-hole region, but with
the extension of the entire C-Br bond is in agreement with their
work.
To our knowledge, this study on PIK-75 is the first that
shows the importance of an intramolecular halogen bond to
stabilize the molecule in a binding-competent conformation and
reduce the entropic penalty upon binding, thus for the first time
explaining the high potency of this molecule.
[5]
[6]
[7]
[8]
E. Beurel, S. F. Grieco, R. S. Jope, Pharmacol Ther 2015, 148,
114-131.
P. Wolle, M. P. Müller, D. Rauh, ACS chemical biology 2018, 13,
496-499.
J. A. Bertrand, S. Thieffine, A. Vulpetti, C. Cristiani, B. Valsasina,
S. Knapp, H. M. Kalisz, M. Flocco, J Mol Biol 2003, 333, 393-407.
aF. H. Allen, J. P. M. Lommerse, V. J. Hoy, J. A. K. Howard, G. R.
Desiraju, Acta Crystallographica Section B-Structural Science
1997, 53, 1006-1016; bC. V. Ramana, Y. Goriya, K. A. Durugkar,
S. Chatterjee, S. Krishnaswamy, R. G. Gonnade, Crystengcomm
2013, 15, 5283-5300.
[9]
Y. C. Zhang, Y. X. Lu, Z. J. Xu, H. R. Ding, W. H. Wu, H. L. Liu,
Struct Chem 2016, 27, 907-917.
[10]
aF. N. Costa, T. F. da Silva, E. M. B. Silva, R. C. R. Barroso, D.
Braz, E. J. Barreiro, L. M. Lima, F. Punzo, F. F. Ferreira, Rsc Adv
2015, 5, 39889-39898; bF. N. Costa, F. F. Ferreira, T. F. da Silva,
E. J. Barreiro, L. M. Lima, D. Braz, R. C. Barroso, Powder Diffr
2013, 28, S491-S509.
[11]
[12]
M. Headgordon, J. A. Pople, M. J. Frisch, Chem Phys Lett 1988,
153, 503-506.
R. Wilcken, M. O. Zimmermann, A. Lange, A. C. Joerger, F. M.
Boeckler, Journal of medicinal chemistry 2013, 56, 1363-1388.
J. S. Murray, P. Lane, P. Politzer, J Mol Model 2009, 15, 723-729.
aO. Fedorov, K. Huber, A. Eisenreich, P. Filippakopoulos, O. King,
A. N. Bullock, D. Szklarczyk, L. J. Jensen, D. Fabbro, J. Trappe, U.
Rauch, F. Bracher, S. Knapp, Chemistry & biology 2011, 18, 67-
76; bJ. Poznanski, M. Winiewska, H. Czapinska, A. Poznanska, D.
Shugar, Acta Biochim Pol 2016, 63, 203-214.
Experimental Section
[13]
[14]
Experimental details can be found in the supporting information.
[15]
R. Desiraju Gautam, P. S. Ho, L. Kloo, C. Legon Anthony, R.
Marquardt, P. Metrangolo, P. Politzer, G. Resnati, K. Rissanen, in
Pure and Applied Chemistry, Vol. 85, 2013, p. 1711.
C. R. Groom, J. C. Cole, Acta Crystallographica Section D 2017,
73, 240-245.
aI. Alkorta, I. Rozas, J. Elguero, J Phys Chem A 1998, 102, 9278-
9285; bS. V. Rosokha, C. L. Stern, J. T. Ritzert, Chem-Eur J 2013,
19, 8774-8788; cG. Cavallo, P. Metrangolo, R. Milani, T. Pilati, A.
Priimagi, G. Resnati, G. Terraneo, Chem Rev 2016, 116, 2478-
2601.
Acknowledgements
[16]
[17]
This work was co-funded by Fundação de Apoio à pesquisa
do Rio de Janeiro (FAPERJ) (Grant No. E-26/202.918/2015, E-
26/200.037/2014), Fundação de Amparo à Pesquisa do Estado
de São Paulo (FAPESP) (Grant No. 2015/26233-7), Conselho
Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
(Grant No 304872/2013-0, 307664/2015-5, 302861/2014-9,
402289/2013-7 and 311291/2015-5), Instituto Nacional de
[18]
P. Politzer, J. S. Murray, T. Clark, Top Curr Chem 2015, 358, 19-
42.
Fármacos
e
Medicamentos (INCT-INOFAR) (Grant No
465.249/2014),Coordenação de Aperfeiçoamento de Pessoal de
This article is protected by copyright. All rights reserved.

10.1002/anie.201804917
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Roberta Tesch[a], Christian Becker[b],
Matthias Philipp Müller[b], Michael
Edmund Beck[c], Lena Quambusch[a],
Matthäus Getlik[b], Jonas Lategahn[b],
Niklas Uhlenbrock[b], Fanny Nascimento
Costa[d], Marcelo D. Polêto[e], Pedro de
Sena Murteira Pinheiro[a], Daniel
Alencar Rodrigues[a], Carlos Maurício
R. Sant’Anna[a,f], Fabio Furlan
Text for Table of Contents
Ferreira[d], Hugo Verli[e], Carlos Alberto
Manssour Fraga[a],* and Daniel Rauh[b],
*
Page No. – Page No.
An Unusual Intramolecular Halogen
Bond guides Conformational
Selection
This article is protected by copyright. All rights reserved.