Types Of Binding Modes Research Articles

Targeting MET: Discovery of Small Molecule Inhibitors as Non-Small Cell Lung Cancer Therapy.

MET has been considered as a promising drug target for the treatment of MET-dependent diseases, particularly non-small cell lung cancer (NSCLC). Small molecule MET inhibitors with mainly three types of binding modes (Ia/Ib, II, and III) have been developed. In this Review, we provide an overview of the structural features, activation mechanism, and dysregulation pathway of MET and summarize progress on the development and discovery strategies utilized for MET inhibitors as well as mechanisms of acquired resistance to current approved inhibitors. The insights will accelerate discovery of new generation MET inhibitors to overcome clinical acquired resistance.

Intermolecular interactions involving the N-heterocyclic carbene and its heavier analogues C2H4N2X: (X = C, Si, Ge, Sn, Pb) with YH3F (Y = Si, Ge, Sn, Pb)

The intermolecular complexes formed between imidazol-2-ylidene and its heavy-atom analogues C2H4N2X: (X = C, Si, Ge, Sn, Pb) and YH3F (Y = Si, Ge, Sn, Pb) have been optimized at the MP2/aug-cc-pVTZ level. C2H4N2X: have two electron-rich moieties, one of which is the lone pair on the X atom and the other is the 6π-electron system. Three types of binding modes (type-A, type-B and type-C) can be distinguished for C2H4N2X: according to the locations of YH3F. The type-A and type-B complexes can be located for C2H4N2C:···YH3F system, and the E int values of the type-A complexes are much larger than those of the type-B complexes. The type-A, type-B and type-C complexes can be located for the other four systems, and the E int values of these complexes go in the order type-B > type-C > type-A. The binding strength of the type-A complexes becomes weaker, and that of the type-B and type-C complexes becomes stronger with the increase of the X atomic number for C2H4N2X:···YH3F system, which can be clarified by the MEP maps of C2H4N2X:. The NBO, AIM and SAPT analysis was employed to explore the nature of the interactions in these complexes.

Nondirected Pd-Catalyzed C–H Perdeuteration and meta-Selective Alkenylation of Arenes Enabled by Pyrazolopyridone Ligands

The development of ligands and the elucidation of their roles in the catalytic cycle are key to achieving high efficiency and selectivity in nondirected transition-metal-catalyzed C–H functionalization. In particular, careful ligand design can enable the functionalization of previously inaccessible substrate positions, which can lead to regiodivergent transformations of common reactants. In this study, a series of pyrazolopyridone (PzPyOH) ligands that can be easily prepared in a single step was developed for the Pd-catalyzed perdeuteration and meta-selective alkenylation of arenes. In this system, the 2-pyridone moiety was incorporated to function as an internal base, facilitating C–H cleavage and rendering C–H activation reversible, even at challenging sp2 C–H bonds, thus enabling perdeuteration. In addition, the reversible activation of the C–H bonds implies that site selectivity is determined during the migratory insertion step in the alkenylation reaction, thereby preferentially functionalizing the meta-positions rather than the typically more reactive ortho- and para-positions of anisole derivatives. Further, the electronic and structural properties of the pyrazole moiety provide flexibility in the ligand binding to Pd, enabling the facile coordination of an alkene coupling partner during alkenylation. In this process, the hydrogen bonding between pyridone and acetate ligands was crucial to stabilize intermediates, allowing for different types of binding modes, including L,L- and L,X-type bidentate and monodentate binding. Kinetic and computational studies support the proposed mechanisms for perdeuteration and alkenylation, and the findings reveal crucial factors in the design of ligands for Pd-catalyzed C–H functionalization, which will be useful for further development of pyrazole- and pyridone-containing ligands in transition metal catalysis.

Synthesis and Structural Characterization of an Amorphous and Photoluminescent Mixed Eu/Zr Coordination Compound, a Potential Marker for Gunshot Residues

Hydrogels based on mixed zirconium/europium ions and benzene tricarboxylic acid were synthesized by hydrothermal reaction. A solid glass-like material is formed upon drying, showing strong reddish luminescence. The system was characterized by solid-state nuclear magnetic resonance, thermal analyses, and infrared spectroscopy. The results reveal the amorphous character of the structure and the presence of at least four types of binding modes between the metal oxide clusters and benzene tricarboxylic acid. On the other hand, thermogravimetric analysis (TGA) showed high thermal stability, with the material decomposing at temperatures higher than 500 °C. The combination of intense Eu3+ luminescence with large thermal stability makes this material a strong candidate for application as a luminescent red marker for gunshot residue (GSR). As proof of concept, we show the feasibility of this application by performing shooting tests using our compound as a GSR marker. After the shots, the residual luminescent particles could be visualized in the triggered cartridge, inner the muzzle of the firearm, and a lower amount on the hands of the shooter, using a UV lamp (λ = 254 nm). Remarkably, our results also show that the Eu3+ emission for the GSR is very similar to that observed for the original solid material. These characteristics are of huge importance since they provide a chance to use smaller amounts of the marker in the ammunition, lowering the costs of potential industrial manufacturing processes.

Probing the Interaction of Bovine Serum Albumin with Copper Nanoclusters: Realization of Binding Pathway Different from Protein Corona

With an aim to understand the interaction mechanism of bovine serum albumin (BSA) with copper nanoclusters (CuNCs), three different types CuNCs having chemically different surface ligands, namely, tannic acid (TA), chitosan, and cysteine (Cys), have been fabricated, and investigations are carried out in the absence and presence of protein (BSA) at ensemble-averaged and single-molecule levels. The CuNCs, capped with different surface ligands, are consciously chosen so that the role of surface ligands in the overall protein-NCs interactions is clearly understood, but, more importantly, to find whether these CuNCs can interact with protein in a new pathway without forming the "protein corona", which otherwise has been observed in relatively larger nanoparticles when they are exposed to biological fluids. Analysis of the data obtained from fluorescence, ζ-potential, and ITC measurements has clearly indicated that the BSA protein in the presence of CuNCs does not attain the binding stoichiometry (BSA/CuNCs > 1) that is required for the formation of "protein corona". This conclusion is further substantiated by the outcome of the fluorescence correlation spectroscopy (FCS) study. Further analysis of data and thermodynamic calculations have revealed that the surface ligands of the CuNCs play an important role in the protein-NCs binding events, and they can alter the mode and thermodynamics of the process. Specifically, the data have demonstrated that the binding of BSA with TA-CuNCs and Chitosan-CuNCs follows two types of binding modes; however, the same with Cys-CuNCs goes through only one type of binding mode. Circular dichroism (CD) measurements have indicated that the basic structure of BSA remains almost unaltered in the presence of CuNCs. The outcome of the present study is expected to encourage and enable better application of NCs in biological applications.

Structural Insights into the Binding Modes of Viral RNA-Dependent RNA Polymerases Using a Function-Site Interaction Fingerprint Method for RNA Virus Drug Discovery.

The coronavirus disease of 2019 (COVID-19) pandemic speaks to the need for drugs that not only are effective but also remain effective given the mutation rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To this end, we describe structural binding-site insights for facilitating COVID-19 drug design when targeting RNA-dependent RNA polymerase (RDRP), a common conserved component of RNA viruses. We combined an RDRP structure data set, including 384 RDRP PDB structures and all corresponding RDRP–ligand interaction fingerprints, thereby revealing the structural characteristics of the active sites for application to RDRP-targeted drug discovery. Specifically, we revealed the intrinsic ligand-binding modes and associated RDRP structural characteristics. Four types of binding modes with corresponding binding pockets were determined, suggesting two major subpockets available for drug discovery. We screened a drug data set of 7894 compounds against these binding pockets and presented the top-10 small molecules as a starting point in further exploring the prevention of virus replication. In summary, the binding characteristics determined here help rationalize RDRP-targeted drug discovery and provide insights into the specific binding mechanisms important for containing the SARS-CoV-2 virus.

Assessing the information content of structural and protein\u2013ligand interaction representations for the classification of kinase inhibitor binding modes via machine learning and active learning

For kinase inhibitors, X-ray crystallography has revealed different types of binding modes. Currently, more than 2000 kinase inhibitors with known binding modes are available, which makes it possible to derive and test machine learning models for the prediction of inhibitors with different binding modes. We have addressed this prediction task to evaluate and compare the information content of distinct molecular representations including protein–ligand interaction fingerprints (IFPs) and compound structure-based structural fingerprints (i.e., atom environment/fragment fingerprints). IFPs were designed to capture binding mode-specific interaction patterns at different resolution levels. Accurate predictions of kinase inhibitor binding modes were achieved with random forests using both representations. The performance of IFPs was consistently superior to atom environment fingerprints, albeit only by less than 10%. An active learning strategy applying information entropy-based selection of training instances was applied as a diagnostic approach to assess the relative information content of distinct representations. IFPs were found to capture more binding mode-relevant information than atom environment fingerprints, leading to highly predictive models even when training instances were randomly selected. By contrast, for atom environment fingerprints, the derivation of accurate models via active learning depended on entropy-based selection of informative training compounds. Notably, higher information content of IFPs confirmed by active learning only resulted in small improvements in global prediction accuracy compared to models derived using atom environment fingerprints. For practical applications, prediction of binding modes of new kinase inhibitors on the basis of chemical structure is highly attractive.

Formation of mononuclear and polynuclear d-block metal complexes from 1,4,7-tris(3-hydroxypropyl)-1,4,7-triazacyclononane: crystal structures, spectroscopic studies, and magnetic properties

Four new d-block metal complexes formulated as [NiII(H3thptacn)]Cl2·H2O (1), [MnIV(thptacn)]ClO4 (2), [CuII3(Hthptacn)2](ClO4)2 (3), and [CdII2(H3thptacn)2Cl2][B(C6H5)4]2 (4) were obtained from the macrocyclic ligand 1,4,7-tris(3-hydroxypropyl)-1,4,7-triazacyclononane (H3thptacn) either through solvent diffusion or by evaporation of their solutions. These complexes were characterized by single crystal X-ray structural determination, elemental analysis, and routine spectroscopic methods. Complexes 1 and 2 exhibit similar mononuclear structures with the metal centers being surrounded by both the backbone nitrogen atoms and the pendant coordinating alcohol/alkoxide groups. Complex 3 is a linear trinuclear cluster, where three Cu(II) centers are combined together by the bridging alkoxide groups in a centro-symmetric pattern. Two chloride groups join two Cd(II) atoms each chelated by one triply protonated ligand H3thptacn to afford dinuclear compound 4 with a symmetry center. When coordinating to different d-block metals, the macrocyclic ligand exhibits four types of binding modes with various dissociation status on its pendant alcohol groups and different numbers of these pendant groups participating in coordination. The magnetic measurements revealed significant zero-field splitting for mononuclear Ni(II) and Mn(IV) complexes. A moderate antiferromagnetic interaction between the neighboring Cu(II) centers governs the magnetic properties of 3 with J = −166(3) cm−1.

93 Spectroscopic investigation of methylene blue binding to DNA

The interaction of methylene blue (MB) with DNA has been investigated by UV absorption spectra, Fluorescence spectra and UV-melting method. Analysis of the results of the melting experiments shows that melting temperature (T m) of the complexes increases with the [total ligand]: DNA ratio (r) at two concentrations of Na+ (2 mM Na+ and 20 mM Na+) providing support for conclusion that MB is a stabilizer of DNA helix structure. By contrast, the shapes of dependences of width of transition (ΔT) on r at low and high [Na+] are different which points to the existence of different types of binding modes of MB with DNA. UV-spectroscopy experiments and fluorescence spectra indicated that the binding modes of MB with DNA depended on r. At high r (r > 0.25), remarkable hypochromic effect with no shift of λ max in the absorption spectra of MB was observed. The fluorescence of MB was quenched which indicated that MB was bound to phosphate groups of DNA by electrostatic interaction. At low r ratios (r < 0.2), the absorption spectra of MB upon increasing the concentration of DNA showed gradually decrease in the peak intensities with a red shift. This phenomenon is usually associated with molecular intercalation into the base stack of the ds-DNA. Using the Scatchard’s model, the complex formation constants for MB with DNA were determined: the binding constant K ≈ 6.5 × 105 and binding site size n ≈ 4. Obtained data are not typical for intercalation model of ligands to DNA. Moreover, comparison between these data and our early experimental results of interaction of ethidium bromide with DNA made it possible to suggest that this binding type of MB is, more probably, semi-intercalation mode (Vardevanyan et al., 2003). This conclusion is in accordance with the analysis of the model structures of MB–DNA complexes which clearly shows the importance of solvent contributions in suggested structural form (Tong et al., 2010).

Structural Studies of β-Carbonic Anhydrase from the Green Alga Coccomyxa: Inhibitor Complexes with Anions and Acetazolamide

The β-class carbonic anhydrases (β-CAs) are widely distributed among lower eukaryotes, prokaryotes, archaea, and plants. Like all CAs, the β-enzymes catalyze an important physiological reaction, namely the interconversion between carbon dioxide and bicarbonate. In plants the enzyme plays an important role in carbon fixation and metabolism. To further explore the structure-function relationship of β-CA, we have determined the crystal structures of the photoautotroph unicellular green alga Coccomyxa β-CA in complex with five different inhibitors: acetazolamide, thiocyanate, azide, iodide, and phosphate ions. The tetrameric Coccomyxa β-CA structure is similar to other β-CAs but it has a 15 amino acid extension in the C-terminal end, which stabilizes the tetramer by strengthening the interface. Four of the five inhibitors bind in a manner similar to what is found in complexes with α-type CAs. Iodide ions, however, make contact to the zinc ion via a zinc-bound water molecule or hydroxide ion — a type of binding mode not previously observed in any CA. Binding of inhibitors to Coccomyxa β-CA is mediated by side-chain movements of the conserved residue Tyr-88, extending the width of the active site cavity with 1.5-1.8 Å. Structural analysis and comparisons with other α- and β-class members suggest a catalytic mechanism in which the movements of Tyr-88 are important for the CO2-HCO3 - interconversion, whereas a structurally conserved water molecule that bridges residues Tyr-88 and Gln-38, seems important for proton transfer, linking water molecules from the zinc-bound water to His-92 and buffer molecules.

Dialkylaluminium‐, ‐Gallium‐, and ‐Indium‐Based Poly‐Lewis Acids with a 1,8‐Diethynylanthracene Backbone

Potential host systems based on a rigid 1,8-diethynylanthracendiyl backbone were synthesised by treatment of 1,8-diethynylanthracene with the Group 13 trialkyls AlMe(3), GaMe(3), InMe(3), AlEt(3) and GaEt(3). The resulting products were characterised by IR and multinuclear NMR spectroscopy, elemental analyses and determination of their crystal structures by X-ray diffraction. The compounds are dimeric in the solid state and comprise two M(2)C(2) heterocycles. Depending on the steric demand of the alkyl substituents at the metal atom, different types of binding modes were observed, which can be classified to lie between the ideals of side-on coordination with almost linear primary M-C≡C units and the 3c-2e coordination with symmetrically bridging alkynyl units in M-C-M bonds. As a solution in THF the dimers are broken into monomers and some are found to undergo ligand scrambling reactions.

Thermodynamics of Polyethylenimine-DNA Binding and DNA Condensation

In this study, polyethylenimine (PEI) binding to DNA was examined by isothermal titration calorimetry. Two types of binding modes were found to describe the interactions between these polyelectrolytes in buffers and in water. One type of binding involves PEI binding to the DNA groove because the enthalpy change of this binding mode is positive, and PEI is deprotonated to bind to DNA. Another likely binding mode involves external binding of PEI to the DNA phosphate backbone, accompanied with DNA condensation. The enthalpy change is negative and PEI is protonated when it binds to DNA in this mode. The intrinsic enthalpy change of first binding mode is 1.1 kJ/mol and −0.88 kJ/mol for the second binding mode. This result implies that the PEI is rearranged from the groove to the phosphate backbone of DNA when DNA is condensed. The mechanism of DNA condensation caused by PEI is discussed in this study.

Controlling the Structure of Manganese(II) Phosphates by the Choice and Ratio of Organophosphate and Auxiliary Ligands

Tetranuclear manganese(II) phosphates [Mn(dipp)(bpy)](4)4 H(2)O (1) and [Mn(4)(dmpp)(2)(dmppH)(4)(bpy)(4)(H(2)O)(2)]H(2)O (2) have been prepared from Mn(OAc)(2)4 H(2)O and 2,6-diisopropylphenyl phosphate (dippH(2)) or 2,6-dimethylphenyl phosphate (dmppH(2)) in the presence of 2,2'-bipyridine (bpy). In contrast, the reaction between [Mn(bpy)(2)(OAc)(ClO(4))]H(2)O and dippH(2) affords [Mn(bpy)(2)(dippH)](2)2 ClO(4)2 CH(3)OH (3). The reactions of Mn(OAc)(2)4 H(2)O, dippH(2), and pyridine (py) or 3,5-dimethylpyrazole (dmpz) in CH(3)CN under reflux afford hexanuclear complexes [Mn(6)(dipp)(6)(py)(8)]2CH(3)CN (4) and [Mn(6)(dipp)(6)(dmpz)(6)(AcOH)(2)]2 H(2)O (5), respectively. Although compounds 1 and 2 are tetrameric, the former is a closed cubane-like structure resembling the D4R secondary building unit of zeolites, whereas the latter exists in a staircase structure with fused Mn(2)O(4)P(2) rings. The core structure of 3 contains a Mn(2)O(4)P(2) eight-membered ring that resembles the S4R building block of zeolites. Single-crystal X-ray diffraction studies reveal that compounds 4 and 5 have a similar core structure and differ from each other by the neutral ligands coordinated to manganese ions. All six phosphate ligands exist in a doubly deprotonated [(RO)PO(3) (2-)] form and exhibit two types of binding modes [5.222] and [3.111]. An interesting feature of compounds 1-5 is that although they are oligonuclear complexes, there is an absence of oxido bridges. The magnetic properties of compounds 1-5 have been investigated in the temperature range 5-298 K, and it was found that all the compounds obey the Curie law.

Synthesis and characterization of a bis-μ,η 1-carboxylate-bridged dinuclear manganese(II) complex containing a tetradentate tripodal ligand, N-(benzimidazol-2-ylmethyl)iminodiacetic acid

The dinuclear Mn(II) complex, [Mn 2(Hbida) 2(H 2O) 2], was prepared using a tetradentate tripodal ligand, N-(benzimidazol-2-ylmethyl)iminodiacetic acid (H 3bida) which has two carboxylate and one benzimidazole groups. The manganese ions are doubly bridged using μ,η 1-bridging monodentate carboxylate oxygen atoms. The Mn–Mn bond distance of 3.446 Å in the complex is comparable to that observed in the active site of the native manganese arginase enzyme (3.30 Å). The geometry of the complex with four carboxylates in two different types of binding modes, non-bridging monodentate and μ,η 1-type bridging monodentate, mimics the active site structure of manganese arginase. The magnetic properties of the complex show a coupling constant of J = −0.471(1) cm −1, which is consistent with weakly coupled antiferromagnetic Mn II ( S = 5/2) centers. The cyclic voltammograms of the Mn(II) complex in DMF show irreversible oxidation occurring around 570 mV (versus Ag/AgCl).

Interaction of trivalent lanthanide cations with nitrate anions: a quantum chemical investigation of monodentate/bidentate binding modes

We report ab initio quantum mechanical calculations on LnIII(NO3−)n (n = 1–3) and Ln(NO3)3(H2O)m (m = 4–6) complexes to compare the monodentate s. bidentate binding mode of nitrate anions to trivalent lanthanide cations (LaIII, EuIII and LuIII) in the gas phase. In all LnIII(NO3−)n complexes studied, bidentate coordination is preferred (by about 30 kcal mol−1 for n = 1 and 20 kcal mol−1 for n = 3). In the Ln(NO3)3(H2O)m aggregates, however, where the first coordination shell is saturated, the two types of binding modes become of similar energy, leading to different coordination numbers (CNs) and distributions of first and second shell water molecules. For instance, for La(NO3)3(H2O)6, CN ranges from 9 (3 monodentate nitrates + 6 water) to 10 (3 bidentate nitrates + 4 water) or 11 (3 bidentate nitrates + 5 water). Thus, at some point, adding water to the second or to the first shell becomes isoenergetic. As the cation becomes smaller, the preference for monodentate nitrate binding increases, due to avoided repulsions in the first coordination sphere. Thus, water coordination to the lanthanide cations may induce a change of anion coordination mode and of coordination number. The fact that in solid state structures bidentate binding is dominant thus does not result from a marked intrinsic preference.

Molecular recognition of amino acid esters by porphyrinatozinc(II): observation of a new binding mode

Molecular recognition of amino acid ethyl esters (guest) by 5-(2-carboxylphenyl)-10,15,20-triphenylporphyrinatozinc(II) (host 1) was investigated using UV–Vis spectrophotometric titration method. The host–guest binding mode was studied by 1H NMR and it was found that the carbonyl group of the guest coordinates to the Zn atom of host 1 and the amino group of the guest forms hydrogen-bonding with the carboxyl group of host 1. This is a new type of binding mode which had not been observed for previous metalloporphyrin–amino acid ester recognition systems.

Competitive cooperative bindings of a small ligand to a linear homopolymer. I. Extension of the ising model to the case of two competitive interactions.

AbstractThe theoretical study of the cooperative binding of a small ligand to a linear homopolymer is extended to systems in which two different complexes can form. The binding isotherms are derived under the assumption that the cooperative interactions exist only between molecules belonging to the same type of binding mode and are limited to nearest neighbors (Ising model). The binding to a single‐stranded chain is first considered and two extreme cases are studied: (1) the two complexes can form independently from each other (model of independent classes of binding sites); (2) only one class of binding site exists, each possessing two different states of complexation (three‐state model).Binding to a double‐helical chain is also considered. Three simple types of competition between the different modes of binding are distinguished. The corresponding models are defined as: (1) the model of independent classes of binding sites; (2) the model of monoexclusive interactions between the different kinds of complexes (the symmetric and asymmetric cases are both considered); (3) the model of biexclusive interactions. The comparative study of the different cases shows that the binding isotherms are very similar at large polymer‐to‐ligand concentration ratios, while they can be very different at low polymer‐to‐ligand ratios. This can be used to obtain information on the mechanism of dye binding to nucleic acids by equilibrium studies as shown in a subsequent paper.