Metal-coordinating Groups Research Articles

On the hunt for metalloenzyme inhibitors: Investigating the presence of metal-coordinating compounds in screening libraries and chemical spaces.

Metalloenzymes play vital roles in various biological processes, requiring the search for inhibitors to develop treatment options for diverse diseases. While compound library screening is a conventional approach, the exploration of virtual chemical spaces housing trillions of compounds has emerged as an alternative strategy. In this study, we investigated the suitability of selected screening libraries and chemical spaces for discovering inhibitors of metalloenzymes featuring common ions (Mg2+, Mn2+, and Zn2+). First, metal-coordinating groups from ligands interacting with ions in the Protein Data Bank were extracted. Subsequently, the prevalence of these groups in two focused screening libraries (Life Chemicals' chelator library, comprising 6,428 compounds, and Otava's chelator fragment library, with 1,784 fragments) as well as two chemical spaces (GalaXi and REAL space, containing billions of virtual products) was investigated. In total, 1,223 metal-coordinating groups were identified, with about a quarter of these groups found within the examined libraries and spaces. Our results indicate that these can serve as valuable starting points for drug discovery targeting metalloenzymes. In addition, this study suggests ways to improve libraries and spaces for better success in finding potential inhibitors for metalloenzymes.

MESPEUS: a database of metal coordination groups in proteins.

MESPEUS is a freely accessible database which uses carefully selected metal coordination groups found in metalloprotein structures taken from the Protein Data Bank. The database contains geometrical information of metal sites within proteins, including 40 metal types. In order to completely determine the metal coordination, the symmetry-related units of a given protein structure are taken into account and are generated using the appropriate space group symmetry operations. This permits a more complete description of the metal coordination geometry by including all coordinating atoms. The user-friendly web interface allows users to directly search for a metal site of interest using several useful options, including searching for metal elements, metal-donor distances, coordination number, donor residue group, and structural resolution. These searches can be carried out singly or in combination. The details of a metal site and the metal site(s) in the whole structure can be graphically displayed using the interactive web interface. MESPEUS is automatically updated monthly by synchronizing with the PDB database. An investigation for the Mg-ATP interaction is given to demonstrate how MESPEUS can be used to extract information about metal sites by selecting structure and coordination features. MESPEUS is available at http://mespeus.nchu.edu.tw/.

(Keynote) N-Heterocyclic Carbene-coated Gold Nanoparticles and Luminescent Quantum Dots

N-heterocyclic carbenes (NHCs) have generated much interest for use as versatile metal-coordinating groups, since they were first synthesized by Arduengo and coworkers in 1991. NHC molecules can be considered as L-type ligands, because they share their non-bonding electron pairs with the σ-accepting orbital of transition metals, and this endows them with strong coordination interactions. NHC-appended molecules have recently been actively exploited as potentially effective ligands for the surface passivation of various colloidal nanomaterials.We investigate the coordination interactions between a few representative colloidal nanocrystals, including gold nanoparticles (AuNPs) and luminescent quantum dots (QDs), and a NHC-based polymer ligand. The latter presents multiple NHC groups and several short poly (ethylene glycol) (PEG) chains as solubilizing blocks. We find that our NHC-decorated ligands rapidly coordinate onto both sets of nanocrystals, which we attribute to their soft Lewis base nature. These ideally match the soft Lewis acid character of transition metal colloid surfaces, promoting strong coordination bonding through soft‐soft interaction. We combine NMR spectroscopy, fluorescence spectroscopy, high-resolution transmission electron microscopy supplemented with dynamic light scattering to characterize the nature of the binding interactions. Furthermore, the long-term stability of the NHC-stabilized nanocolloids have been tested after phase transfer to water, a highly challenging chemical venue for such groups, due to the moisture sensitive nature of NHC molecules. Data show that our NHC-polymer-stabilized AuNPs and QDs exhibit long-term colloidal stability in buffer media while preserving their optical and fluorescing properties, with no sign of degradation or aggregation build up for at least one year of storage. We will discuss the ligand design and synthesis, characterization of the polymer-stabilized nanocrystals under various conditions, with a particular focus on the beneficial effects of ligand multi-coordination interactions onto the nanocolloid surfaces.

Stimuli-Responsive DNA Binding by Synthetic Systems.

DNA is the molecule responsible for the storage and transmission of the genetic information in living organisms. The expression of this information is highly regulated. In eukaryotes, it is achieved mainly at the transcription level thanks to specialized proteins called transcription factors (TFs) that recognize specific DNA sequences, thereby promoting or inhibiting the transcription of particular genes. In many cases, TFs are present in the cell in an inactive form but become active in response to an external signal, which might modify their localization and DNA binding properties or modulate their interactions with the rest of the transcriptional machinery. As a result of the crucial role of TFs, the design of synthetic peptides or miniproteins that can emulate their DNA binding properties and eventually respond to external stimuli is of obvious interest. On the other hand, although the B-form double helix is the most common DNA secondary structure, it is not the only one with an essential biological function. Guanine quadruplexes (GQs) have received considerable attention due to their critical role in the regulation of gene expression, which is usually associated with a change in the GQ conformation. Thus, the development of GQ probes whose properties can be controlled using external signals is also of significant relevance.In this Account, we present a summary of the recent efforts toward the development of stimuli-responsive synthetic DNA binders with a particular emphasis on our own contributions. We first introduce the structure of B and GQ DNAs, and some of the main factors underlying their selective recognition. We then discuss some of the different approaches used for the design of stimulus-mediated DNA binders. We have organized our discussion according to whether the interaction takes place with duplex or guanine quadruplex DNAs, and each section is divided according to the nature of the stimulus (i.e., physical or chemical). Regarding physical stimuli, light (through the incorporation of photolabile protecting groups or photoisomerizable agents) is the most common input for the activation/deactivation of DNA binding events. With respect to chemical signals, the use of metals (through the incorporation of metal-coordinating groups in the DNA binding agent) has allowed the development of a wide range of stimuli-responsive DNA binders. More recently, redox-based systems have also been used to control DNA interactions.This Account ends with a "Conclusions and Outlook" section highlighting some of the general lessons that have been learned and future directions toward further advancing the field.

Synthesis and properties of metal organic frameworks with novel metal-imidazolate secondary building units

Metal-organic frameworks (MOFs) are a class of inorganic-organic hybrid materials and have potential applications in many fields such as gas adsorption and storage, catalysis, ion exchange and separation, chemical sensing and so on. It has attracted a great deal of chemists attention. Moreover, the development of new secondary building units (SBUs) is of great importance for the synthesis of MOFs. In this work, we choose 2-(1-hydroxy-ethyl)-3H-benzo- imidazole-5-carboxylic acid (Hebimc) as organic ligand, which is a trifunctional imidazolate derivative comprising metal coordination groups and diverse functional sites. In this ligand, the imidazolate unit can provide μ2-bridging coordination mode to form zeolitic MOFs, the hydroxy unit could offer active site for further reactions, the benzene ring may offer π-π interaction with guest molecules for fascinating structures, and the carboxy unit also could coordinate to metal center. So far, MOFs assembled by Hebimc ligand and auxiliary dicarboxylic ligands have not been reported yet. By employing the Hebimc ligand and introduce auxiliary dicarboxylic ligands to assemble with different transition metal salts, respectively, four MOFs from one-dimensional (1D) to three-dimensional (3D), namely, Zn2(Hebimc)4 ( 1 ), Zn2(Hebimc)2(BDC)∙ x G( 2 ,BDC=terephthalic acid, G=guest molecule), Zn2 (Hebimc)2 (NDC)∙ x G ( 3, NDC=2,6-naphthalene diacid), Zn8(Hebimc)6(DOBDC)(OH)2(H2O)2∙ x G( 4 ,DOBDC=2,5-dih-ydroxyterephthalic acid), have been synthesized under different reaction conditions. 1 was synthesized by the reaction of Hebimc and ZnSiF6·6H2O in H2O at 100°C for 3 d (yield: 40% based on Hebimc); 2 was prepared by the reaction of Hebimc and BDC and ZnSiF6·6H2O in isopropanol/water (6:3, v:v) at 100°C for 3 d (yield: 65% based on Hebimc); 3 was prepared by the reaction of Hebimc, NDC, pyrazine, tetraethylammonium bromide (TEAB) and Zn(NO3)2·6H2O in N , N -dimethyl formamide (DMF)/water (3:1.5, v:v) at 120°C for 3 d (yield: 78% based on Hebimc); 4 was prepared by the reaction of Hebimc, DOBDC, pyrazine, triphenylphosphine and Zn(NO3)2·6H2O in DMF/water (6:1.5, v:v) at 120°C for 3 d (yield: 50% based on Hebimc). Single crystal X-ray diffraction was used to characterize their structures. It is noted that Hebimc ligands in this structures are chelate coordinate to metal centers to form Zn2(Hebimc)2 SBUs, which is unusual in MOFs. 1 crystallized in orthorhombic P2 1 2 1 2 1 space group and exhibited 1D chain connected by N–H…O hydrogen bonds into a supermolecular structure. By introducing auxiliary dicarboxylic ligands, two 2D layers 2 and 3 are obtained. 2 crystallized in monoclinic P2 1/ c space group and exhibited 2D (4,4)- sql layer. There is no obvious interaction between the layers, packing a 3D accumulation structure in the ABAB way. 3 crystallized in triclinic P-1 space group and exhibited an 2D (4,4)- sql layer, packing a 3D accumulation structure in the AA way. Under the inducement of the ligand DOBDC, a pillar-layer 3D structure 4 is obtained. 4 crystallized in monoclinic C2 / c space group and can be simplified as a (4,5)-connected network with the point symbol (42.53.65)2(52.64). Besides, hydroxy-functional neutral compound 4 shows an obvious degradation effect on photocatalysis of crystal violet aquous after loading Ag nanoparticles (NPs). These results demonstrated that the mixed ligand approach is a successful route for the construction of MOFs.

EDTA diversifies its role as a metal detector

Calcium, magnesium, and zinc are divalent metal ions essential for good health. Other divalent metals, such as cadmium, lead, and arsenic, are toxic. Turning to common metal-chelating agents, researchers have found that they can use nuclear magnetic resonance spectroscopy and magnetic resonance imaging to quantitatively sense and distinguish among all these metals in blood serum (Anal. Chem. 2016, DOI: 10.1021/acs.analchem.6b03546). Gil G. Westmeyer of the Technical University of Munich and colleagues labeled the metal-coordinating carboxyl groups of ethylenediaminetetraacetic acid (EDTA) or ethylene glycol bis(2-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA) with 13C. When either of the compounds binds the metals, 13C NMR spectra show well-separated chemical shifts that allow the researchers to distinguish between the metals. For example, they were able to quantitate millimolar concentrations of Ca2+ in human serum in the presence of competing concentrations of Mg2+. The researchers were further abl...

A surrogate for selectivity

Metal-coordinating groups are widely used to direct C–H functionalization. Now the combination of an alkene hydrosilylation, C–H activation and C–Si oxidation has been used to achieve a formal 1,4-dioxygenation of alkenes.

A multifunctional amphiphilic polymer as a platform for surface-functionalizing metallic and other inorganic nanostructures.

We designed a new set of polymer ligands that combine multiple metal-coordinating groups and short polyethylene glycol (PEG) moieties in the same structure. The ligand design relies on the controlled grafting of a large number of amine-terminated histamines and PEG short chains onto a poly(isobutylene-alt-maleic anhydride) backbone, via a one-step nucleophilic addition reaction. This addition reaction is highly efficient, can be carried out in organic media and does not require additional reagents. We show that when imidazole groups are used the resulting polymer ligand can strongly ligate onto metal nanostructures such as nanoparticles (NPs) and nanorods (NRs) made of gold cores. The resulting polymer-coated NPs and NRs exhibit good colloidal stability to pH changes and added electrolytes. This constitutes a departure from the use of thiol-based ligands to coordinate on Au surfaces. The present chemical approach also opens up additional opportunities for designing hydrophilic and reactive platforms where the polymer coating can be adjusted to various metal and metal oxide surfaces by simply modifying or combining the addition reaction with other metal coordinating groups. These could include iron oxide NPs and semiconductor QDs. These polymer-capped NPs and NRs can be used to develop biologically-active platforms with potential use for drug delivery and sensing.

Multiple supported Keggin-type polyoxometalate polymer built upon weak copper–oxygen interaction

Two inorganic–organic hybrid compounds based on Keggin-type polyoxotungstates have been synthesized and characterized. X-ray single crystal analysis indicated that both compounds [Cu(bpe)]6[HCu0.5W12O40]·6H2O (1) and [Cu(bpe)]6[PWV3WVI9O40]·8H2O (2) (bpe=trans-1,2-di-(4-pyridyl)-ethylene) exhibit high-dimensional frameworks constructed from Keggin-type anions and from secondary metal coordination groups of Cu-bpe. It is interesting that in two compounds there are eight Cu-bpe fragments to be anchored around one anion via relatively weak Cu–O interactions (Cu–O=2.482–2.812Å), respectively. Compound 1 is a three-dimensional framework; while compound 2 represents a two-dimensional structure. The luminescent property, cyclic voltammetry and thermal stability of 1–2 have been investigated.

Syntheses, Crystal Structures and Properties of Two New Transition-Metal-Centered Heteropolytungstates

Two one-dimensional transition-metal-centered polyoxotungstates, that is, [Cu(en)2][Cu(en)2(H2O)][Cu(en)(phen)][CuW12O40]·3H2O (1) (en = ethylenediamine, phen = phenanthroline) and [Cu(en)2]2[Cu(en)2(H2O)]2[V5.8W7.2O40(VO)4]·3H2O (2) have been synthesized hydrothermally and structurally characterized by elemental analyses, IR spectroscopy, electrochemical analysis, thermogravimetric analysis and X-ray single crystal diffraction. Single-crystal structural analysis reveals that both of them represent one-dimensional structures constructed from transition-metal-centered Keggin-type polyanions bridged by secondary metal coordination groups of Cu-ligand. Noticeably, compound 1 exhibits a helical chain-liked structure, and the anion is coordinated by three Cu-ligand units, representing a copper-centered and tri-supported Keggin structure. In compound 2, the polyoxoanion [V5.8W7.2O40(VO)4]8− represents a V-centered tetra-capped pseudo-Keggin structure, and is coordinated by four Cu-ligand units. The three-dimensional supramolecular structures of compounds 1 and 2 are constructed through intermolecular hydrogen bonding interactions. The electrochemical and thermalstable properties of 1 and 2 are also studied. The results show the redox properties of polyoxotungstates are retained in title polymers.

A new layered vanadate complex with a tunnel structure: [{Cu(mbpy)}2V8O21] (mbpy = 4,4′-dimethyl-2,2′-bipyridine)

A new vanadate with a tunnel structure [{Cu(mbpy)}2V8O21] (1) (mbpy = 4,4′-dimethyl-2,2′-bipyridine) has been synthesized hydrothermally. X-ray crystal analysis reveals that 1 exhibits a layered structure constructed from {V8O21} n layers grafted with secondary metal coordination groups of Cu-mbpy. The thermogravimetric analysis and electrochemistry of 1 are also reported.

A novel 2D layer structure constructed from sandwich-type transition metal substituted tungstates and nickel coordination fragments: {[Ni(enMe) 2] 2[Ni(enMe) 2(H 2O)] 2[As 2W 18Ni 4(enMe) 2O 68]}·2H 3O·2H 2O

A novel polyoxometalate {[Ni(enMe) 2] 2[Ni(enMe) 2(H 2O)] 2[As 2W 18Ni 4(enMe) 2O 68]}·2H 3O·2H 2O ( 1) (enMe = 1,2-propylenediamine) has been synthesized and characterized, which is the first high-dimensional structure constructed from sandwich-type transition metal substituted tungstates and transition metal coordination groups.

Asymmetry in 13C−13C COSY Spectra Provides Information on Ligand Geometry in Paramagnetic Proteins

The relative intensity of Calpha-C' cross-peaks in homonuclear 13C COSY spectra depends on the relaxation properties of Calpha and C' spins, which, in the proximity of a paramagnetic center, are related to the metal-to-carbon distance. Their quantitative analysis has lead, for the cerium-substituted dicalcium protein, calbindin D9k, to the straightforward identification of peaks arising from metal-coordinating groups. The monodentate or bidentate metal binding mode of carboxylates was identified directly via NMR.

The architecture of metal coordination groups in proteins.

A set of tables is presented and a survey given of the architecture of metal coordination groups in a representative set of protein structures from the Protein Data Bank [Bernstein et al. (1977), J. Mol. Biol. 112, 535-542; Berman et al. (2000), Nucleic Acids Res. 28, 235-242]. The structures have been determined to a resolution of 2.5 A or better; the metals considered are Ca, Mg, Mn, Fe, Cu, Zn, Na and K, with particular emphasis on Ca and Zn and the exclusion of haem groups and Fe/S clusters; the proteins are a representative set in which none has more than 30% sequence identity with any other. In them the metal is coordinated by several donor groups from different amino-acid residues in the protein chain and often also by water or other small molecules. The tables, for approximately 600 metal coordination groups, include information on the conformations of the protein chain in the region around the metal and reliability indicators. They illustrate the wide variety of coordination numbers, chelate-loop sizes and other properties and the different characteristics of different metals. They show that glycine has a particular significance in the position adjacent to a donor residue, especially in Ca coordination groups. They also show that metal coordination does not appear to lead to significant distortions of the torsion angles phi, psi from their normally allowed values. Very few metal coordination groups occur more than once in the representative set and when they do they are usually related in fold and function; they have similar but not necessarily identical conformations. However, individual chelate loops, for example Zn(-C-X-X'-C-), in which both cysteines are coordinated to Zn through S, and X and X' are any amino acids, are repeated frequently in many different and unrelated proteins. Not all chelate loops with the same composition have the same conformation, but for smaller loops there are usually one or two strongly preferred and well defined conformations. Quite frequently more than one metal coordination group is associated with one protein chain; these proteins are identified.

Hydrothermal synthesis and structure of one-dimensional Co(dien) 2(VO 3) 3·(H 2O) (dien=diethylenetriamine)

One-dimensional Co(dien) 2(VO 3) 3·(H 2O) was prepared from the hydrothermal reaction of NH 4VO 3, Co 2O 3, diethylenetriamine (dien) and H 2O at 130 °C. The compound crystallizes in the monoclinic system, space group P2 1/ c with a=16.1581(6) Å, b=8.7006(3) Å, c=13.9893(4) Å, β=103.1483(11)°, V=1915.13(11) Å 3, Z=4, and R 1=0.0268 for 3060 observed reflections. Single crystal X-ray diffraction revealed that the structure is composed of infinite one-dimensional chains formed by corner-sharing VO 4 tetrahedra with Co(dien) 3+ complex cations and crystallization water molecules occupying the interchain positions, which are held together to a three-dimensional network via extensive hydrogen-bonding interactions. The compound, with a new zig-zag conformation of metavanadate chains, is the first example of vanadium oxides incorporating trivalent transition metal coordination groups. Other characterizations by elemental analysis, IR and thermal analysis are also described.

Protonation state of Asp120 in the binuclear active site of the metallo-beta-lactamase from Bacteroides fragilis.

The determination of the protonation state of enzyme active sites may be crucial for the investigation of their mechanism of action. In the bizinc beta-lactamase family of enzymes, no consensus has been reached on the protonation state of a fully conserved amino acid present in the active site, Asp120. To address this issue, we carry out here density functional theory (DFT) calculations on large models (based on Bacteroides fragilis X-ray structure) which include the metal coordination polyhedron and groups interacting with it. Our calculations suggest that Asp120 is ionized. The relevance of this finding for site-directed mutagenesis experiments on the 120 position and on the mechanism of action is discussed.

π-Conjugated multiporphyrin box via self-assembly of an ethynylene-bridged zinc porphyrin dimer

An ethynylene-bridged zinc porphyrin dimer bearing metal-coordinating groups, such as bis[{5-(4-pyridyl)-15-(3,5-didodecyloxyphenyl)porphyrinato}zinc] Z2, self-assembles in CHCl 3 to form a rectangular-shaped supramolecular nano box, in which all the Z2 units preferentially adopt a planar conformation with a syn-parallel geometry as for the pyridyl groups.

Regioselective Oxidation of Steroids by a Manganese Porphyrin Carrying Metal Coordinating Groups

A manganese porphyrin having four 2,2′-bipyridyl groups on its meso positions was synthesized. In the presence of Cu 2+ ions it catalyzes the regioselective oxidation of steroid substrates carrying auxiliary metal coordinating groups.

Review: Multipoint binding and heterogeneity in immobilized metal affinity chromatography

Studies carried out using engineered proteins clearly demonstrate that adsorption to derivatized surfaces involves multiple interactions between functional groups on the protein and complementary sites distributed on the surface. The fact that adsorption involves multipoint interactions has important implications for the design of separations processes and for the interpretation of heterogeneity in biological recognition phenomena. Increasing the density of surface metal sites (immobilized copper ions) is found to be functionally equivalent to increasing the number of metal-coordinating groups on the protein (histidines and deporotonated amines), m in that both processes increase the likelihood of simultaneous interactions between the protein and the surface. A consequence of multiple-site interactions is a significant in crease in protein binding affinity that depends on the arrangement of surface sites. A protein will show the highest affinity for arrangements of surface sites which best match its own pattern of functioal groups and will show lower affinity for less optimal arrangements, resulting in binding that is inherently heterogeneous. We have found that reversible protein adsorption in immobilized metal affinity chromatography (IMAC) is described by the Temikin model, which characterizes binding heterogeneity by a uniform distribution of binding energies over the population of surface binding sites. (c) 1995 John Wiley & Sons, Inc.