Fluorine Scan of Inhibitors of the Cysteine Protease Human Cathepsin L: Dipolar and Quadrupolar Effects in the π‐Stacking of Fluorinated Phenyl Rings on Peptide Amide Bonds

The π‐stacking of fluorinated benzene rings on protein backbone amide groups was investigated, using a dual approach comprising enzyme–ligand binding studies complemented by high‐level quantum chemical calculations. In the experimental study, the phenyl substituent of triazine nitrile inhibitors of human cathepsin L (hCatL), which stacks onto the peptide amide bond Gly67?Gly68 at the entrance of the S3 pocket, was systematically fluorinated, and differences in inhibitory potency were measured in a fluorimetric assay. Binding affinity is influenced by lipophilicity (clog P), the dipole and quadrupole moments of the fluorinated rings, but also by additional interactions of the introduced fluorine atoms with the local environment of the pocket. Generally, the higher the degree of fluorination, the better the binding affinities. Gas phase calculations strongly support the contributions of the molecular quadrupole moments of the fluorinated phenyl rings to the π‐stacking interaction with the peptide bond. These findings provide useful guidelines for enhancing π‐stacking on protein amide fragments.     

Stacking Interactions of Heterocyclic Drug Fragments with Protein Amide Backbones

Stacking interactions can be important enthalpic contributors to drug binding. Among the less well‐studied stacking interactions are those occurring between an arene and the π‐face of an amide group. Given the ubiquity of heterocycles in drugs, combined with the abundance of amides in the protein backbone, optimizing these noncovalent interactions can provide a potential route to enhanced drug binding. Previously, Diederich et al. (ChemMedChem 2013 , 8, 397–404) studied stacked dimers of a model amide with a set of 18 heterocycles, showing that computed interaction energies correlate with the dipole moments of the heterocycles and providing guidelines for the optimization of these interactions. We considered stacked dimers of the same model amide with a larger set of 28 heterocycles common in pharmaceuticals, by using more robust ab initio methods. While the overall trends in these new data corroborate many of the results of Diederich et al., these data provide a more refined view of the nature of amide stacking interactions. We present a robust scoring function for amide stacking interaction energies based on the molecular dipole moment and strength of the electric field above the arene.     

Efficient adsorptive desulfurization by task‐specific porous organic polymers

A task‐specific mesoporous organic polymer (TSPOP) with unique features like good porosity and rich aromatic phenyl groups was facilely made and utilized as a promising adsorptive desulfurization absorbent for the first time. The material exhibits an efficient saturated adsorption of dibenzothiophene (DBT), as high as 111.1 mg g^?1. In addition, the intrinsic mesoporous skeleton of TSPOP gave rise to a facile incorporation of uniform Ag(I) species inside the network which facilitated the uptake of organosulfur compounds. A significantly higher saturated DBT adsorption for Ag(I)‐loaded TSPOP reaches 203.7 mg g^?1 via a multiple‐site interaction. A detailed model study based on the density functional calculation provides a deeper understanding of the origin of this high activity. In addition to the π–π stacking between DBT and phenyl rings, there exists an additional π‐complexation adsorption with Ag(I) ions, thus, significantly improving the DBT capture performance. © 2016 American Institute of Chemical Engineers AIChE J, 62: 1740–1746, 2016     

Augmenting Structure-Based Design with Experimental Protein-Ligand Interaction Data: Molecular Recognition,Interactive Visualization,and Rescoring

The previously introduced ratio of frequencies (R_F) framework provides statistically sound information on the relative interaction preferences of atoms in crystal structures. By applying the methodology to protein-ligand complexes, we can investigate the significance of interactions that are employed in structure-based drug design. Here, we revisit three aspects of molecular recognition in the light of the R_F framework, namely stacking interactions of heteroaromatic rings with protein amide groups, interactions of acidified C−H groups, and interaction differences between syn and anti lone pairs of carboxylate groups. In addition, we introduce a highly interactive visualization tool that facilitates design idea generation in structure-enabled drug discovery projects. Finally, we show that applying the R_F analysis as a simple rescoring tool after docking improves enrichment factors for the DUD−E diverse targets subset supporting the relevance of our approach.     

The Physical Properties and Self‐Assembly Potential of the RFFFR Peptide

The self‐assembly of fibers from peptides has attracted a tremendous amount of attention due to its many applications, such as in drug‐delivery systems, in tissue engineering, and in electronic devices. Recently, the self‐assembly potential of the designer peptide RFFFR has been reported. Here it is experimentally verified that the peptide forms fibers that are entangled and form solid spheres without water inside. Upon dilution below the critical fiber concentration, the fibers untangle and become totally separated prior to dissolution. These structures readily bind thioflavin T, resulting in a characteristic change in fluorescent properties consistent with β‐sheet‐rich amyloid structures with aromatic/hydrophobic grooves. The circular dichroism spectroscopy data are dominated by a π→π* transition, thus indicating that the fibers are stabilized by π‐stacking. Contrary to what was expected, the dissolution of the spheres/fibers results in increasing fluorescence anisotropy over time. This is explained in terms of HomoFRET between phenylalanine residues with a T‐shaped π‐stacking mode, which was determined in another study to be the dominant mode through atomistic simulations and semiempirical calculations. Kelvin probe force microscopy measurements indicate that the spheres and fibers have a conductivity comparable to that of gold. Hence, these self‐assembled structures might be applicable in organic solid‐state electronic devices. The dissolution properties of the spheres further suggest that they might be used as drug‐delivery systems.     

Compatibility,crystallinity and mechanical properties of poly(lactic acid)‐poly(ether‐block‐amide) based copper nanocomposites

Binary and ternary composites of poly(lactic acid) (PLA), poly(ether‐block‐amide) (PEBAX) and copper nanoparticles were prepared by melt blending in an internal mixer. Compatibility and molecular interactions between the three components of the nanocomposites were evaluated using scanning electron microscopy and Fourier transform infrared spectroscopy. It was found that the carbonyl groups of the PLA and copper nanoparticles interact. Also, PLA and PEBAX are compatible and develop molecular interactions between the C=O of PLA and the C=O and NH of PEBAX, forming dipole–dipole bonds and hydrogen bonds. The compatibility and molecular interaction between PLA and PEBAX are reduced by copper nanoparticles. The reduction of compatibility between PLA and PEBAX produced a lower storage modulus and lower strain at break in the ternary systems than in the blend PLA‐PEBAX. Copper nanoparticles enhanced the crystallinity of PLA. PLA responded more strongly to the nucleating effect of copper when PEBAX was added indicating a synergistic effect. The strain at break of PLA was enhanced by the addition of PEBAX but was severely reduced by the presence of nanoparticles. © 2020 Society of Chemical Industry     

Structure-activity studies in a family of beta-hairpin protein epitope mimetic inhibitors of the p53-HDM2 protein-protein interaction

Inhibitors of the interaction between the p53 tumor-suppressor protein and its natural human inhibitor HDM2 are attractive as potential anticancer agents. In earlier work we explored designing beta-hairpin peptidomimetics of the alpha-helical epitope on p53 that would bind tightly to the p53-binding site on HDM2. The beta-hairpin is used as a scaffold to display energetically hot residues in an optimal array for interaction with HDM2. The initial lead beta-hairpin mimetic, with a weak inhibitory activity (IC(50)=125 microM), was optimized to afford cyclo-(L-Pro-Phe-Glu-6ClTrp-Leu-Asp-Trp-Glu-Phe-D-Pro) (where 6ClTrp=L-6-chlorotryptophan), which has an affinity almost 1,000 times higher (IC(50)=140 nM). In this work, insights into the origins of this affinity maturation based on structure-activity studies and an X-ray crystal structure of the inhibitor/HDM2(residues 17-125) complex at 1.4 A resolution are described. The crystal structure confirms the beta-hairpin conformation of the bound ligand, and also reveals that a significant component of the affinity increase arises through new aromatic/aromatic stacking interactions between side chains around the hairpin and groups on the surface of HDM2.     

Immobilization of the Laccases from Trametes versicolor and Streptomyces coelicolor on Single‐wall Carbon Nanotube Electrodes: A Molecular Dynamics Study

In this work, we investigate the immobilization of laccases from Trametes versicolor (TvL) and the small laccase (SLAC) from Streptomyces coelicolor on single‐wall carbon nanotube (SWCNT) surfaces. SLAC may potentially offer improved adsorption on the electrode, thus improving bioelectrocatalytic activity via direct electron transfer (DET). Laccase immobilization on SWCNTs is achieved non‐covalently with a molecular tether (1‐pyrene butanoic acid, succinimidyl ester) that forms an amide bond with an amine group on the laccase surface while the pyrene coordinates to the SWCNT by π–π stacking. In our approach, density functional theory calculations were first used to model the interaction energies between SWCNTs and pyrene to validate an empirical force field, thereafter applied in molecular dynamics (MD) simulations. In the simulated models, the SWCNT was placed near the region of the (type 1) Cu(T1) atom in the laccases, and in proximity to other regions where adsorption seems likely. Calculated interaction energies between the SWCNTs and laccases and distances between the SWCNT surface and the Cu(T1) atom have shown that SWCNTs adsorb more strongly to SLAC than to TvL, and that the separation between the SWCNTs and Cu(T1) atoms is smaller for SLAC than for TvL, having implications for improved DET.     

1-(3-biaryloxy-2-oxopropyl)indole-5-carboxylic acids and related compounds as dual inhibitors of human cytosolic phospholipase A2α and fatty acid amide hydrolase

Cytosolic phospholipase A2α (cPLA2α) and fatty acid amide hydrolase (FAAH) are enzymes that have emerged as attractive targets for the development of analgesic and anti-inflammatory drugs. We recently reported that 1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid (5) is a dual inhibitor of cPLA2α and FAAH. Structure-activity relationship studies revealed that substituents at the indole 3- and 5-positions and replacement of the indole scaffold of this compound by other heterocycles strongly influences the inhibitory potency against cPLA2α and FAAH, respectively. Herein we report the effect of variation of the 4-octyl residue of 5 and an exchange of its carboxylic acid moiety by some bioisosteric functional groups. Several of the compounds assayed were favorably active against both enzymes, and could therefore represent agents with improved analgesic and anti-inflammatory qualities in comparison with selective cPLA2 α and FAAH inhibitors.     

Modeling and biological investigations of an unusual behavior of novel synthesized acridine-based polyamine ligands in the binding of double helix and G-quadruplex DNA

Three novel 2,7-substituted acridine derivatives were designed and synthesized to investigate the effect of this functionalization on their interaction with double-stranded and G-quadruplex DNA. Detailed investigations of their ability to bind both forms of DNA were carried out by using spectrophotometric, electrophoretic, and computational approaches. The ligands in this study are characterized by an open-chain (L1) or a macrocyclic (L2, L3) framework. The aliphatic amine groups in the macrocycles are joined by ethylene (L2) or propylene chains (L3). L1 behaved similarly to the lead compound m-AMSA, efficiently intercalating into dsDNA, but stabilizing G-quadruplex structures poorly, probably due to the modest stabilization effect exerted by its protonated polyamine chains. L2 and L3, containing small polyamine macrocyclic frameworks, are known to adopt a rather bent and rigid conformation; thus they are generally expected to be sterically impeded from recognizing dsDNA according to an intercalative binding mode. This was confirmed to be true for L3. Nevertheless, we show that L2 can give rise to efficient π-π and H-bonding interactions with dsDNA. Additionally, stacking interactions allowed L2 to stabilize the G-quadruplex structure: using the human telomeric sequence, we observed the preferential induction of tetrameric G-quadruplex forms. Thus, the presence of short ethylene spacers seems to be essential for obtaining a correct match between the binding sites of L2 and the nucleobases on both DNA forms investigated. Furthermore, current modeling methodologies, including docking and MD simulations and free energy calculations, provide structural evidence of an interaction mode for L2 that is different from that of L3; this could explain the unusual stabilizing ability of the ligands (L2>L3>L1) toward G-quadruplex that was observed in this study.     

Optical and vibrational studies on single walled carbon nanotubes/short oligo‐para‐methoxy‐toluene composite

In a solution state, an oligophenylene prepared by electrochemical oxidation of para‐methoxy‐toluene exhibited luminescence in the violet‐to‐blue region. However, in a solid state, a clear red shift was observed as a signature of a supramolecular π‐stacking interaction between oligomer chains. In a de‐doped state, by chemical reduction, a fine structure in the form of two peaks was observed and luminescence intensity was strongly improved. When mixed with single walled carbon nanotubes (SWNTs), a quenching in the luminescence intensity accompanied by a slight blue shift of the PL peak of the nanocomposite was observed. This implies the shortening of the oligomer's effective π‐conjugation length caused by the added amount of SWNTs. A charge transfer in the photo‐excited state was also noted. The interaction taking place between the two materials was supported by optical infrared absorption and Raman scattering measurements and then a functionalizing mechanism was proposed. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

The water relaxation in polymers containing the amide group

The low temperature water relaxation of synthetic polymers containing the amide group is usually attributed to the motion of a water-polymer complex in the amorphous region. According to Puffr and Sebenda the complex is formed by water and amide group in the stoichiometric ratio 1.5. Elastin, an insoluble protein of vessels and ligaments, seems the ideal polymer for testing the model, being practically free of polar side groups and having a glass transition at 200°C, so that its “water peak” can be easily investigated. Calorimetric investigations show that the molar ratio for “bound water-amide group” is indeed 1.5, as predicted by the model. The activation energy of the “water peak” is very close, for the “dry” protein, to that of nylons, but it decreases with increasing hydration to a limit of 9 kcal/mole. The results give additional support to the traditional interpretation of the polyamide beta relaxation and to the Puffr and Sabenda model for the interaction of water and amide groups in synthetic polymers.     

Role of amphiphilic dopants on the shape and properties of electrically conducting polyaniline‐clay nanocomposite

The role of functionality and rigidity of the amphiphilic dopants on the morphology and electrical property of the polyaniline‐clay nanocomposites (PANICNs) were studied by preparing polyaniline (PANI) and PANICNs using five structurally different amphiphilic dopants having backbone—phenyl, naphthyl, alicyclic, and alkyl groups. Effect of the size and functionality of the dopant on the extent of intercalation/exfoliation, morphology, thermal stability, and phase transitions were studied. PANICNs exhibited different morphologies such as nano/micro granules, rods, nanotubes, aggregated layers/clusters, and rice grain for PANICN‐2,6‐naphthalene sulphonic acid, PANICN‐para‐toluene sulphonic acid, PANICN‐stearic acid, PANICN‐dodecyl benzene sulphonic acid, and PANICN‐camphor sulphonic acid, respectively. X‐ray diffraction, Fourier transform infrared, and scanning electron microscopic studies showed that the self‐assembled nano/microstured aggregates were formed by the combined effect of many noncovalent interactions such as phenyl–phenyl stacking, hydrogen bonding, ion–dipole interaction, π–π stacking, and electrostatic layer‐by‐layer self‐assembling. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009.     

Performance improvement on the cold flow properties of crude oil with high asphaltene by adjusting the polarity of the third monomer in polymers

Asphaltenes and waxes are the primary factors affecting the cold flow properties of crude oil. In this paper, based on the binary polymer of acrylate-maleic anhydride (PM₂₂-MA), different third polar groups of acrylamide, N-(hydroxymethyl) acrylamide, N-phenylacrylamide (NPA), and styrene (SM) were introduced to synthesize a series of ternary pour point depressants (PPDs) to explore the effect of asphaltene on the cold flow properties of Xijiang (XJ) crude oil. Thereinto, PM₂₂-MA-NPA containing amide group and benzene ring exhibited the best depressive effect, which decreased pour point by 14°C at 1500 ppm. The mechanism of interaction of the polar groups in PPDs with asphaltene was studied. The polar groups could form stronger hydrogen bonds with asphaltene, delaying the asphaltene macromolecule bonding, allowing the synergistic effect of PPDs and asphaltene to be better utilized to improve the cold flow properties of crude oil. Furthermore, the dipole moment magnitude and electron cloud density were calculated with Gaussian. It was found that the polar group with a dipole moment magnitude of 3.2244 debye and an electron cloud density ranging from −1.6364 to 1.9944 eV was the most suitable third polar monomer for the PPDs of XJ crude oil.     

Delocalized π‐electrons in 2‐oxazoline rings resulting in negatively charged nitrogen atoms: revealing the selectivity during the initiation of cationic ring‐opening polymerizations

The inventory of the single‐crystal X‐ray structures of aliphatic and aromatic 2‐oxazolines, namely 2‐nonyl‐2‐oxazoline, 2,2′‐tetramethylenebis(2‐oxazoline) and 2‐phenyl‐2‐oxazoline, reveals significant delocalization of π‐electrons along the N? C? O segment. The delocalization of π‐electrons is stabilized by inductive and resonance contributions of the side‐chains; in 2‐phenyl‐2‐oxazoline, also π‐arene interactions between the benzene ring and the C? N and the C? O bond stabilize the crystalline phase. This delocalization gives a partial negative charge to the nitrogen atom and a partial positive charge to the oxygen atom. The partial negative charge of the nitrogen atom makes this atom the exclusive reaction partner also for highly reactive non‐selective cations, which explains the regioselectivity of electrophilic attacks in cationic ring‐opening polymerizations. Copyright © 2011 Society of Chemical Industry     

Preparation of All Polyester‐Based Semi‐IPN Elastomers Containing Self‐Associative or Non‐Associative Guest Chains via Post‐Blending Cross‐Linking

Mechanical properties of semi‐interpenetrating polymer network (semi‐IPN) elastomers consisting of chemical networks and self‐associative/non‐associative guest chains are demonstrated. Amorphous low T_g polyesters with thiol side groups (PE‐SH) are first synthesized by melt polycondensation. PE‐SH are then converted to polyesters containing COOH side groups (PE‐COOH) and amide side groups (PE‐amide) through Michael addition reaction of thiol groups with acrylic acid and acrylamide, respectively. Homogeneous semi‐IPN elastomers are obtained by thermal cross‐linking for bulk mixtures of PE‐COOH and PE‐amide in the presence of diepoxy cross‐linkers, where COOH and epoxy groups are reacted to form chemical cross‐links while the amide units form self‐complementary hydrogen bonds. Another sample containing non‐associative chains is also prepared by using polyester with N,N‐dimethylamide units, instead of PE‐amide. Dynamic mechanical analysis reveals that guest chain incorporation systematically brings plateau modulus reduction and a unique relaxation with higher tan δ value depending on the fraction and nature of guest chains. Tensile properties are also affected by the fraction and nature of guest chains; the incorporation of hydrogen bonded chains are beneficial to enhance breaking elongation and toughness without the sacrifice of maximum stress. The knowledge found in this work will be thus beneficial for creating tough soft materials with damping applications.     

An ionic liquid‐based polymer with π‐stacked structure as all‐solid‐state electrolyte for efficient dye‐sensitized solar cells

An ionic liquid based polymer, poly(1‐ethyl‐3‐(acryloyloxy)hexylimidazolium iodide) (PEAI), was synthesized and employed as electrolyte to fabricate all‐solid‐state dye‐sensitized solar cells. The photophysical properties of PEAI were studied by UV–vis absorption spectroscopy and photoluminescence spectroscopy. PEAI exhibited significant hypochromism and red shift in UV–vis absorption spectra and large Stokes shifts in photoluminescence spectra, indicating the formation of a novel π‐stacked structure in which the imidazolium rings in the side chain were stacked. Without iodine in its preparation, DSC with PEAI electrolyte achieved a conversion efficiency of 5.29% under AM 1.5 simulated solar light irradiation (100 mW cm^?2). The side‐chain imidazolium π‐π stacking in PEAI played a key role in the holes transport from the photoanode to the counter electrode. Both the open‐circuit voltage and short‐circuit current density showed decreases with the increase in the content of iodine in PEAI electrolyte. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Photochemical Control of DNA Structure through Radical Disproportionation

Photolysis of an aryl sulfide‐containing 5,6‐dihydropyrimidine ( 1 ) at 350 nm produces high yields of thymidine and products resulting from trapping of a 5,6‐dihydrothymidin‐5‐yl radical by O₂ or thiols. Thymidine is believed to result from disproportionation of the radical pair originally generated from C? S bond homolysis of 1 on the microsecond timescale, which is significantly shorter than other photochemical transformations of modified nucleotides into their native forms. Duplex DNA containing 1 is destabilized, presumably due to disruption of π‐stacking. Incorporation of 1 within the binding site of the restriction endonuclease EcoRV provides a photochemical switch for turning on the enzyme's activity. In contrast, 1 is a substrate for endonuclease VIII and serves as a photochemical off switch for this base excision repair enzyme. Modification 1 also modulates the activity of the 10–23 DNAzyme, despite its incorporation into a nonduplex region. Overall, dihydropyrimidine 1 shows promise as a tool to provide spatiotemporal control over DNA structure on the miscrosecond timescale.     

Novel poly(ester amide)s from glycine and L‐lactic acid by an easy and cost‐effective synthesis

Novel low molecular weight poly(ester amide)s based on glycine and l ‐lactic acid with interest for the biomedical field were successfully prepared by interfacial polymerization, which is an easy and fast polymerization method. Preparation of the α‐amino acid based diamine, the l ‐lactic acid based diacyl chlorides and the poly(ester amide)s was carried out in the absence of catalysts. The structure of the different poly(ester amide)s was confirmed by ¹H NMR and Fourier transform infrared spectroscopies. The thermal behaviour of the synthesized poly(ester amide)s was evaluated by simultaneous thermal analysis, differential scanning calorimetry and dynamic mechanical thermal analysis. It was found that both the incorporation of an l ‐lactic acid oligomeric segment and the change in its central unit have an important influence on the thermal characteristics of the poly(ester amide)s. These novel poly(ester amide)s can be used as building blocks for the preparation of more complex structures. © 2013 Society of Chemical Industry