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π‐Hole interactions with nitro aromatic ligands found within protein–ligand complexes. Left: Perspective view of 20 aligned nitro arene ligands (grey wires) and relevant residues (green wires) as found within 20 cyclin‐dependent kinases 2 structures. The ligand shown in capped grey sticks is ligand 6 found in PDB 3r28. The red spheres represent the center of mass of the waters 372, 375, 403 and 743. Middle: Perspective view of 35 aligned nitro arene ligands (grey wires) and relevant residues (green wires) as found within 9 cholera toxin B pentameric structures. The ligand shown in capped grey sticks is ligand 7 found in chain D of 1eei. The red sphere represents the center of mass of all water‐533 O‐atoms. Right: Perspective view of 38 aligned nitro arene ligands (grey wires) and relevant residues (green wires) as found within 2 type II dehydroquinase structures. The ligands shown in capped grey sticks is ligand 8 found in chain T of 4ki7. The green sphere represents the center of mass of all aromatic rings of the Tyr‐24 residues.
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Studying noncanonical intermolecular interactions between a ligand and a protein constitutes an emerging research field. Identifying synthetically accessible molecular fragments that can engage in intermolecular interactions is a key objective in this area. Here, it is shown that so‐called “π‐hole interactions” are present between the nitro moiety...
Citations
... [7] In biological systems, hydrogen bonds (HBs), dipole-dipole and π-π interactions, and coulombic forces [8][9][10] are considered the most frequent intermolecular noncovalent interactions acting to promote and regulate drug action at different levels including absorption, transport, and distribution in the living body, metabolism, pharmacokinetics, pharmacodynamics, and excretion. [8a] More recently, halogen (HaB), [11] chalcogen, [12] spodium [13] and π-hole [14] bonds were also identified as interactions underlying ligand-protein binding, recognition, and function. These achievements have paved the way for new horizons in drug design and discovery. ...
In the last decade, biological processes involving halogen bond (HaB) as a leading interaction attracted great interest. However, although bound iodine atoms are considered powerful HaB donors, few iodinated new drugs were reported so far. Recently, iodinated 4,4’‐bipyridines showed interesting properties as HaB donors in solution and in the solid state. In this paper, a study on the inhibition activity of seven halogenated 4,4’‐bipyridines against malignant melanoma (MM) cell proliferation is described. Explorative dose/response proliferation assays were first performed with three 4,4’‐bipyridines by using four MM cell lines and the normal BJ fibroblast cell line as control. Among them, the A375 MM cell line was the most sensitive, as determined by MTT assays, which was selected to evaluate the antiproliferative activity of all 4,4’‐bipyridines. Significantly, the presence of an electrophilic iodine impacted the biological activity of the corresponding compounds. The 3,3’,5,5’‐tetrachloro‐2‐iodo‐4,4’‐bipyridine showed significant antiproliferation activity against the A375 cell line, and lower toxicity on BJ fibroblasts. Through in silico studies, the stereoelectronic features of possible sites determining the bioactivity were explored. These results pave the way for the utilization of iodinated 4,4’‐bipyridines as templates to design new promising HaB‐enabled inhibitors of MM cell proliferation.
... Nitro substitution in the parent aromatic ring has a positive electrostatic potential which can interact with the proteinscarbonyls, sulfurs, and water via "π−hole interaction". 76 Molecular electrostatic potential studies conducted for MDC and ADC substantiate this result. The presence of amide bonds is another salient feature for a better bioactivity. ...
Novel methylenedioxyphenyl-based amides, especially
N-(4-methoxybenzyl)-6-nitrobenzo-[1,3]-dioxole-5-carboxamide
(MDC) and N-(3-acetylphenyl)-6-nitrobenzo-[1,3]-dioxole-
5-carboxamide (ADC), potential cardiovascular preventive agents,
are successfully synthesized, and their chemical structures are
verified by 1H and 13C NMR, Fourier transform infrared (FT-IR),
high-resolution mass spectrometry (HRMS), and single-crystal Xray
diffraction (SC-XRD) analyses. Data obtained from SC-XRD
reveal that MDC and ADC are both monoclinic molecules with Z =
2 and 4, respectively. From density functional theory (DFT)
calculations, 3.54 and 3.96 eV are the energy gaps of the optimized
MDC and ADC structures, respectively. MDC and ADC exhibit an
electrophilicity index value of more than 1.5 eV, suggesting that they can act as an electrophile, facilitating bond formation with
biomolecules. Hirshfeld surface analysis demonstrates that more than 25% of atomic interactions in both MDC and ADC are from
H···H interactions. Based on pharmacokinetic predictions, MDC and ADC exhibit drug-like properties, and molecular docking
simulations revealed favorable interactions with active site pockets. Both MDC and ADC achieved higher docking scores of −7.74
and −7.79 kcal/mol, respectively, with myeloperoxidase (MPO) protein. From docking results, MPO was found to be most
favorable followed by dipeptidyl peptidase-4 (DPP-4) and α-glucosidase (α-GD). Antioxidant, anti-inflammatory, and in vitro
enzymatic studies of MDC and ADC indicate that MDC is more selective toward MPO and more potent than ADC. The application
of MDC to inhibit myeloperoxidase could be ascertained to reduce the cardiovascular risk factor. This can be supported from the
results of computational docking (based on hydrogen bonding and docking score), in vitro antioxidant and anti-inflammatory
properties, and MPO enzymatic inhibition (based on the percentage of inhibition and IC50 values).
... As mentioned above, HB, dipole-dipole, π-π interactions, and coulombic forces are considered the most frequent noncovalent interactions acting to promote and regulate molecular binding, recognition, and function in chemical and biological environments. However, advancements in theoretical and experimental analysis contributed to deeply revise the scenario of noncovalent interactions, making this field very crowded with the identification of a huge number of new interactions, among them σ-hole interactions like halogen [7][8][9]103], chalcogen bond [10,104], and spodium bond [105], and π-hole bond [106]. ...
In modern pharmaceutical and biomedical research, molecular modeling represents a useful tool to explore
processes and their mechanistic bases at the molecular level. Integrating experimental and virtual analysis is a
fruitful approach to study ligand-receptor interaction in chemical, biochemical and biological environments. In
these fields, molecular docking and molecular dynamics are considered privileged techniques for modeling (bio)
macromolecules and related complexes. This review aims to present the current landscape of molecular modeling
in pharmaceutical and biomedical research by examining selected representative applications published in the
last years and highlighting current topics and trends of this field. Thus, a systematic compilation of all published
literature has not been attempted herein. After a brief overview of the main theoretical and computational tools
used to investigate mechanisms at molecular level, recent applications of molecular modeling in drug discovery,
ligand binding and for studying protein conformation and function will be discussed. Furthermore, specific
sections will be devoted to the application of molecular modeling for unravelling enantioselective mechanisms
underlying the enantioseparation of chiral compounds of pharmaceutical and biomedical interest as well as for
studying new forms of noncovalent interactivity identified in biochemical and biological environments. The
general aim of this review is to provide the reader with a modern overview of the topic, highlighting advancements
and outlooks as well as drawbacks and pitfalls still affecting the applicability of theoretical and
computational methods in the field of pharmaceutical and biomedical research.
... In nitrobenzene, the electron withdrawing effect of the nitro-substitution is evident from the decreased magnitude of negative potential over the phenyl carbon atoms ( −2.7 kcal mol −1 ) and also the increased magnitude of positive potential over the hydrogen atoms ( + 25.3 kcal mol −1 ) The localised region of positive potential (@ + 13.9 kcal mol −1 ) is the π -hole in nitrobenzene which enables the pnicogen bonding, detected by QTAIM and NBO analyses. The location of this π -hole over nitrogen is quite characteristic to nitrogen in NO 2 /NO 3 moieties, owing to their planarity, which in turn is a consequence of the sp 2 hybridization of nitrogen, as has been reported before [40][41][42] . The origin of directionality of the pnicogen bond, due to this π -hole has been discussed by Bauza et al. [43][44] and Mooibroek [45] . ...
... As a result, all compounds remained stably bound to the ERα ligand binding cavity lined by helices H3, H6, S2, and H1 for 500 ns of MD simulations (Figure 4) [31]. In order to identify the crucial interactions defining the binding pose of each ligand, we computed their interaction fingerprint (Table 4), discovering the type of interactions (i.e., H-bonds, charge-dipole, or aromatic interactions) [32] contributing the most to drug stability. Table 4. Fingerprint of the interactions that R-3b, S-3b, R-4a, and S-4a establish to ERα during 500 ns MD simulations. ...
... Conversely, persistent electrostatic interactions are exclusively present in compound 4a due to its polar substituent: the hydroxyl group H-bonds with Glu353 on helix H3 in the R enantiomer. S-4a H-bonds with its nitro group to the same In order to identify the crucial interactions defining the binding pose of each ligand, we computed their interaction fingerprint (Table 4), discovering the type of interactions (i.e., Hbonds, charge-dipole, or aromatic interactions) [32] contributing the most to drug stability. Table 4. Fingerprint of the interactions that R-3b, S-3b, R-4a, and S-4a establish to ERα during 500 ns MD simulations. ...
Despite the significant outcomes attained by scientific research, breast cancer (BC) still represents the second leading cause of death in women. Estrogen receptor-positive (ER+) BC accounts for the majority of diagnosed BCs, highlighting the disruption of estrogenic signalling as target for first-line treatment. This goal is presently pursued by inhibiting aromatase (AR) enzyme or by modulating Estrogen Receptor (ER) α. An appealing strategy for fighting BC and reducing side effects and resistance issues may lie in the design of multifunctional compounds able to simultaneously target AR and ER. In this paper, previously reported flavonoid-related potent AR inhibitors were suitably modified with the aim of also targeting ERα. As a result, homoisoflavone derivatives 3b and 4a emerged as well-balanced submicromolar dual acting compounds. An extensive computational study was then performed to gain insights into the interactions the best compounds established with the two targets. This study highlighted the feasibility of switching from single-target compounds to balanced dual-acting agents, confirming that a multi-target approach may represent a valid therapeutic option to counteract ER+ BC. The homoisoflavone core emerged as a valuable natural-inspired scaffold for the design of multifunctional compounds.
... According to Frontera and Mooibroek, these interactions that can affect the planarity of the rings belong to the class of π-hole pnictogen bonding interactions. 93,94 We extended it to the N···N situation, that is, to the pnictogen interaction, 95,96 and specifically to the ortho-nitrophenyl-2-pyrazolines 2a and 3e. 25 There we used as a criterion the N···N distance, 2.78 and 2.69 Å respectively, stating that ″the sum of the van der Waals radii is 3.16 Å (Kitaigorodsky) and 3.00 (Pauling)″. Since the use of the ΣvdW is rather controversial, 97−101 we turned to another criterion, the orthogonality that we have defined as the lower N2···N4− O3(4) angle; in almost all cases, this angle is <90°but in two cases 2i (93.85°) and 3h (91.61°) they are >90°due to the lack of planarity of the nitro group, another effect of the orthogonal interaction. ...
... 31,32 This group is also abundant in protein ligands. 33 Statistical analysis is an important tool used to understand the favorable geometry of an interaction. Moreover, as this analysis is performed on a large sample of experimentally determined crystal structures, it is a highly effective and reliable technique to understand the favorable geometry of a supramolecular interaction. ...
... Halogen and chalcogen bonding, as examples of ζ-hole interactions, are nowadays frequently used in crystal engineering and catalysis [13,14]. Regarding π-hole interactions, it has been demonstrated that those involving nitro derivatives [15][16][17], nitrate esters [18,19] and even nitrate anion [20] are very relevant dictating their solid state architecture. ...
Two new copper (II) carboxylates viz. [Cu 2 (μ-2-chlorobenzoato-O,O') 4 (2-methoxybenzaldehyde) 2 ] (1) and [Cu(μ-3,5-dinitrobenzoato-CO,O)(μ-3,5-dinitrobenzoato-NO,O)][Cu 2 (μ-3,5-dinitrobenzoato-CO,O′)](μ 1 MeOH) 2 (2) containing 2-chlorobenzoic acid and 3,5-dinitrobenzoic acid respectively were synthesized, and characterized by elemental analyses, spectroscopic methods, topological analysis and single crystal XRD studies. Moreover, the synthesized complexes have been screened for the DNA binding ability through UV-visible and fluorescence spectroscopy indicating moderately strong non-intercalative mode of interaction. Structural studies reveals that compound 1 possess dinuclear paddle-wheel structure whereas compound 2 is 3D polymer. Asymmetric/ monoclinic unit of compound 2 contains a mononuclear unit in combination with a dinuclear entity. DFT calculations combined with QTAIM and NCI plot computational tools have been used to analyze their solid-state supramolecular assemblies focusing on the role of halogen···halogen interactions in 1 and π-hole O···N pnictogen bonding in 2 involving the nitro groups. Finally, the dye adsorption property of the complexes was studied to ascertain their efficacy in removal of toxic dye molecules from aqueous medium. Compound 2 exhibit moderate dye removal efficiency.
... Similar C-H···O interactions have been shown to be stabilizing in nature [14]. Additionally, studies have shown that π-hole interactions are of similar energetic magnitude as C-H···O interactions [28]. The smaller red spot on the mapped d norm surface was O4 interacting with the methyl hydrogens from an adjacent t-butyl group (2.61 Å, d(O4···H14B z , z = 1 − x, 2-y, −1/2 + z). ...
Two polymorphs of a benzoxadiazole derivative were examined to determine the interactions leading to the formation of two distinct crystalline forms. Hirshfeld surface analysis was used to establish and contrast the interactions in the two samples. Fingerprints derived from the surface analysis were used to distinguish and lead the analysis in discovering the different interactions in the two crystals. π interactions, specifically, π-hole interactions with a nitro moiety, were found to play an important role in the formation of the crystal structure. Further, carbonyl interactions and π-stacking contribute to the overall relative stability of the different conformational polymorphs. Calculated energy frameworks were used to help visualize the interactions between molecules in the crystal structure, supported by an understanding of the individual interactions. The experimental data were supplemented with theoretical studies to establish a through understanding of these heterocyclic systems.
... For drugs, many nitrate esters and nitro aromatics are found as ligands in protein structures by π-hole interactions with about −5 kcal/mol interaction energies, which display better inhibition or binding affinity compared to very similar non-nitro analogues and suggest a functional relevance of these π-hole interactions. 65 In EMs, the π-hole interactions are also found in 2,4,6trinitrotoluene, octanitrocubane, as well as other polynitro energetic crystals, 66 while the effect of π-hole interactions on packing modes of EMs is less well studied. ...
