Drug–target interaction prediction by integrating multiview network data

Drug–target interaction (DTI) prediction is a challenging step in further drug repositioning, drug discovery and drug design. The advent of high-throughput technologies brings convenience to the development of DTI prediction methods. With the generation of a high number of data sets, many mathematical models and computational algorithms have been developed to identify the potential drug–target pairs. However, most existing methods are proposed based on the single view data. By integrating the drug and target data from different views, we aim to get more stable and accurate prediction results.In this paper, a multiview DTI prediction method based on clustering is proposed. We first introduce a model for single view drug–target data. The model is formulated as an optimization problem, which aims to identify the clusters in both drug similarity network and target protein similarity network, and at the same time make the clusters with more known DTIs be connected together. Then the model is extended to multiview network data by maximizing the consistency of the clusters in each view. An approximation method is proposed to solve the optimization problem. We apply the proposed algorithms to two views of data. Comparisons with some existing algorithms show that the multiview DTI prediction algorithm can produce more accurate predictions. For the considered data set, we finally predict 54 possible DTIs. From the similarity analysis of the drugs/targets, enrichment analysis of DTIs and genes in each cluster, it is shown that the predicted DTIs have a high possibility to be true.     

Reactions of tea polyphenol four constituents with hydroxyl radical: A pulse radiolytic study

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Capillary electrophoresis methods for the determination of covalent polyphenol–protein complexes

The bioactivities and bioavailability of plant polyphenols including proanthocyanidins and other catechin derivatives may be affected by covalent reaction between polyphenol and proteins. Both processing conditions and gastrointestinal conditions may promote formation of covalent complexes for polyphenol-rich foods and beverages such as wine. Little is known about covalent reactions between proteins and tannin, because suitable methods for quantitating covalent complexes have not been developed. We established capillary electrophoresis methods that can be used to distinguish free protein from covalently bound protein–polyphenol complexes and to monitor polyphenol oxidation products. The methods are developed using the model protein bovine serum albumin and the representative polyphenol (−)epigallocatechin gallate. By pairing capillaries with different diameters with appropriate alkaline borate buffers, we are able to optimize resolution of either the protein–polyphenol complexes or the polyphenol oxidation products. This analytical method, coupled with purification of the covalent complexes by diethylaminoethyl cellulose chromatography, should facilitate characterization of covalent complexes in polyphenol-rich foods and beverages such as wine.     

Capillary electrophoresis methods for the determination of covalent polyphenol–protein complexes

The bioactivities and bioavailability of plant polyphenols including proanthocyanidins and other catechin derivatives may be affected by covalent reaction between polyphenol and proteins. Both processing conditions and gastrointestinal conditions may promote formation of covalent complexes for polyphenol-rich foods and beverages such as wine. Little is known about covalent reactions between proteins and tannin, because suitable methods for quantitating covalent complexes have not been developed. We established capillary electrophoresis methods that can be used to distinguish free protein from covalently bound protein-polyphenol complexes and to monitor polyphenol oxidation products. The methods are developed using the model protein bovine serum albumin and the representative polyphenol (-)epigallocatechin gallate. By pairing capillaries with different diameters with appropriate alkaline borate buffers, we are able to optimize resolution of either the protein-polyphenol complexes or the polyphenol oxidation products. This analytical method, coupled with purification of the covalent complexes by diethylaminoethyl cellulose chromatography, should facilitate characterization of covalent complexes in polyphenol-rich foods and beverages such as wine.     

Drug–protein interaction with Vpu from HIV-1: proposing binding sites for amiloride and one of its derivatives

Vpu is an 81-amino-acid auxiliary protein of the genome of HIV-1. It is proposed that one of its roles is to enhance particle release by self-assembling to form water-filled channels enabling the flux of ions at the site of the plasma membrane of the infected cell. Hexamethylene amiloride has been shown to block Vpu channel activity when the protein is reconstituted into lipid bilayers. In a docking approach with monomeric, pentameric and hexameric bundle models of Vpu corresponding to the transmembrane part of the protein, a putative binding site of hexamethylene amiloride is proposed and is compared with the site for the nonpotent amiloride. The binding mode for both ligands is achieved by optimizing hydrogen bond interactions with serines. Binding energies and binding constants are the lowest for protonated hexamethylene amiloride in the pentameric bundle. Figure The proposed binding site of the Vpu channel blocker hexamethylene amiloride within the lumen of the Vpu bundle. The bundle is a homo-pentamer with each monomer consisting of the first 32 amino acids of Vpu including the transmembrane part of the protein which is encoded by HIV-1. The bundle atoms are shown in their van der Waals representation and the helix backbone in a ribbon representation. Residues Trp-23 and Ser-24 are highlighted as sticks. Hexamethylene amiloride is shown in yellow (C atoms) and blue (N atoms)     

Characterization of the chemical differences between solvent extracts from Pu-erh tea and Dian Hong black tea by CP–Py–GC/MS

Solvent extracts from a type of Pu-erh tea and Dian Hong black tea were characterized by Curie-point pyrolysis–gas chromatography–mass spectroscopy (CP–Py–GC/MS). The ethyl-acetate extracts from both teas showed similar CP–Py–GC/MS results, with main pyrolytic products of carbon dioxide, caffeine, o-phenols, and phthalate esters. During pyrolysis, the n-butanol extract from Pu-erh tea formed carbon dioxide (38.92% of total pyrolytic products), alkaloids (49.7%), and nitrogen oxides (8.38%), as well as a small fraction of esters. The n-butanol extract from Dian Hong tea formed mainly alcohols, amines, esters, phenols, carboxylic acids, and alkaloids. The raw theabrownin extracts (ethanol precipitates) from the two teas produced substantially different CP–Py–GC/MS results. The raw theabrownin extract from Pu-erh tea formed mostly carbon dioxide during pyrolysis, whereas the counterpart extract from Dian Hong tea formed mainly carbon dioxide (48.23%) and nitrogen oxides (35.39%). The 3.5–100 kDa fractions separated from the theabrownin extracts of the two teas showed similar CP–Py–GC/MS results, whereas the fractions <3.5 kDa and >100 kDa formed substantially different pyrolytic products. These results showed that solvent extracts from Pu-erh tea and Dian Hong tea had substantially different chemical compositions and structures. The study suggested that CP–Py–GC/MS can be used to effectively identify chemical differences between tea extracts.     

Massively parallel spin–orbit configuration interaction

We describe a new approach to incorporating quantum effects into chemical reaction rate theory using quantum trajectories. Our development is based on the entangled trajectory molecular dynamics method for simulating quantum processes using trajectory integration and ensemble averaging. By making dynamical approximations similar to those underlying classical transition state theory, quantum corrections are incorporated analytically into the quantum rate expression. We focus on a simple model of quantum decay in a metastable system and consider the deep tunneling limit where the classical rate vanishes and the process is entirely quantum mechanical. We compare our approximate estimate with the well-known WKB tunneling rate and find qualitative agreement.     

Delaying Anticancer Drug Delivery by Self-Assembly and Branching Effects of Minimalist Dendron–Drug Conjugates

Self-assembly of a covalently-bound lipophilic drug to a dendronic scaffold for making organic nanoparticles is reported as a proof of concept in nanovectorization. A minimalist structural approach with a small PEG-dendron conjugated to paclitaxel (PTX), incorporating safe succinic and gallic acids, is efficient to provide the expected anticancer bioactivity, but also significantly retards and targets intracellular delivery of PTX in 2D and 3D lung cancer cell cultures. A branching effect of dendrons is crucial, when compared to linear PTX conjugates. Transmission electron microscopy (TEM) and dynamic light-scattering (DLS) studies indicate the formation of stable, low-disperse nanoparticles at 10⁻⁵ m in H₂0, which could also be responsible for the biological effects. An ultrasensitive LC-MS/MS method was used for the determination of intracellular PTX concentration over time, along with the survival rates of cancer cells. Similarly, cell survival assays were successfully correlated to a 3D cell culture with spheroids for mimicking tumors, when treated with PTX conjugates. Our work opens the way to a full evaluation program required for new chemical entities.     

Curie-point pyrolysis–gas chromatography–mass spectroscopic analysis of theabrownins from fermented Zijuan tea

Zijuan tea theabrownins (ZTTBs) was extracted from a type of fermented Zijuan tea and separated into fractions according to molecular weight. The extract was found to contain predominantly two fractions: <3.5 kDa and >100 kDa. These two fractions were analyzed for chemical composition, structural characteristics by Curie-point pyrolysis–gas chromatography–mass spectroscopy (CP-Py–GC/MS). The affects of pyrolysis temperature on pyrolytic products were also investigated. The fraction >100 kDa produced 50 GC/MS peaks during pyrolysis at 280 °C, 70 peaks at 386 °C, and 134 peaks at 485 °C. Fourteen of the products formed at 280 °C, 12 of those formed at 386 °C, and 21 of those formed at 485 °C were identified with match qualities of greater than 80%. The fraction <3.5 kDa gave 51 peaks during pyrolysis at 280 °C, 99 peaks at 386 °C, and 257 peaks at 485 °C. Six products formed at 280 °C, four products formed at 386 °C, and 61 products formed at 485 °C were identified with match qualities of greater than 80%. Pyrolysis temperatures of 485 °C and 386 °C were found suitable for the two fractions respectively. CP-Py–GC/MS revealed that, the fraction >100 kDa mainly consisted of phenolic pigments, esters, proteins, and polysaccharides, while the fraction <3.5 kDa contained no polysaccharide. CP-Py–GC/MS is an effective tool for the composition difference and structural characteristics of ZTTBs as well as other complex macromolecular plant pigments.     

JR 400–NaAOT interaction: a detailed thermodynamic study of polymer–surfactant interaction bearing opposite charges

The present study entails interaction between the cationic polymer N,N-dimethylhydroxyethyl cellulose (JR 400) and the double-tailed anionic surfactant Na-bis-2-ethyhexylsulphosuccinate (NaAOT). This oppositely charged polymer and surfactant are expected to cause coacervation and precipitation; hence, we have observed formation of thick solution similar to diluted gel at [JR 400]?~?0.01 and 0.10 %?w/v in aqueous solution. Viscometry, conductometry, tensiometry, and microcalorimetry techniques are used to monitor the interaction process. The results are explained in the light of both intrachain and interchain linking by way of NaAOT reverse micelle formation. Adsorption of NaAOT monomers onto the charged side chains of the polymer shields interchain electrostatic repulsion, leading to the formation of hydrophobic microdomains and microscopic heterogeneity in the solution. The morphologies of the domains depend on the level of addition of NaAOT in the system. The different stages of physiochemical changes that arise in solution have been identified by the use of different techniques, and correlations of the results have been attempted in terms of pragmatic models.     

The Fe-N-C Nanozyme with Both Accelerated and Inhibited Biocatalytic Activities Capable of Accessing Drug–Drug Interactions

Emerging as a cost-effective and robust enzyme mimic, nanozymes have drawn increasing attention with broad applications ranging from cancer therapy to biosensing. Developing nanozymes with both accelerated and inhibited biocatalytic properties in a biological context is intriguing to peruse more advanced functions of natural enzymes, but remains challenging, because most nanozymes are lack of enzyme-like molecular structures. By re-visiting and engineering the well-known Fe-N-C electrocatalyst that has a heme-like Fe-N_x active sites, herein, it is reported that Fe-N-C could not only catalyze drug metabolization but also had inhibition behaviors similar to cytochrome P450 (CYP), endowing it a potential replacement of CYP for preliminary evaluation of massive potential chemicals, drug dosing guide, and outcome prediction. In addition, in contrast to electrocatalysts, the highly graphitic framework of Fe-N-C may not be obligatory for a competitive CYP-like activity.     

Orthogonal Cysteine Protection Enables Homogeneous Multi-Drug Antibody–Drug Conjugates

A strategy for the preparation of homogeneous antibody–drug conjugates (ADCs) containing multiple payloads has been developed. This approach utilizes sequential unmasking of cysteine residues with orthogonal protection to enable site-specific conjugation of each drug. In addition, because the approach utilizes conjugation to native antibody cysteine residues, it is widely applicable and enables high drug loading for improved ADC potency. To highlight the benefits of ADC dual drug delivery, this strategy was applied to the preparation of ADCs containing two classes of auristatin drug-linkers that have differing physiochemical properties and exert complementary anti-cancer activities. Dual-auristatin ADCs imparted activity in cell line and xenograft models that are refractory to ADCs comprised of the individual auristatin components. This work presents a facile method for construction of potent dual-drug ADCs and demonstrates how delivery of multiple cytotoxic warheads can lead to improved ADC activities. Lastly, we anticipate that the conditions utilized herein for orthogonal cysteine unmasking are not restricted to ADCs and can be broadly utilized for site-specific protein modification.     

Behavior of a Chitosan–Drug System during Diffusion Processes

The process of water vapor sorption by medical chitosan films and the release of nonelectrolyte drugs from these films are investigated. It is shown that the nonelectrolyte drugs are unable to modify the chitosan matrix and cannot provide a prolonged drug release. The modification of chitosan–drug films, for example, by isothermal annealing or transition from the salt form of chitosan to the base one, is required to decelerate the release of drugs from the films.     

Photochemical Reactions in the Synthesis of Protein–Drug Conjugates

The ability to modify biologically active molecules such as antibodies with drug molecules, fluorophores or radionuclides is crucial in drug discovery and target identification. Classic chemistry used for protein functionalisation relies almost exclusively on thermochemically mediated reactions. Our recent experiments have begun to explore the use of photochemistry to effect rapid and efficient protein functionalisation. This article introduces some of the principles and objectives of using photochemically activated reagents for protein ligation. The concept of simultaneous photoradiosynthesis of radiolabelled antibodies for use in molecular imaging is introduced as a working example. Notably, the goal of producing functionalised proteins in the absence of pre-association (non-covalent ligand-protein binding) introduces requirements that are distinct from the more regular use of photoactive groups in photoaffinity labelling. With this in mind, the chemistry of thirteen different classes of photoactivatable reagents that react through the formation of intermediate carbenes, electrophiles, dienes, or radicals, is assessed.     

HPIC–UV–ICP–SFMS study of the interaction of cisplatin with guanosine monophosphate

Interaction of cis-[Pt(NH₃)₂Cl₂] (cisplatin) with 5′-guanosine monophosphate (5′-GMP) has been investigated for the first time by on-line coupling of high performance ion chromatography (HPIC) to inductively coupled plasma sector field mass spectrometry (ICP–SFMS). The time-dependent reaction course of the cisplatin-5′-GMP system was followed after incubation under simulated physiological conditions by monitoring the decrease in the concentration of 5′-GMP and the increase in the concentration of formed adducts, on the basis of speciation analysis. Because of the two-step mechanism an intermediate mono adduct was observed together with the major product, the bis adduct cis-[Pt(NH₃)₂(GMP)₂]^2–. The data obtained correlated well with those from earlier studies employing orthogonal techniques such as capillary electrophoresis (CE). Furthermore, HPIC–ICP–SFMS provided unambiguous stoichiometric information about the major GMP-adduct. For this purpose the platinum-to-phosphorus ratio was determined by simultaneously measuring ³¹P and ¹⁹⁵Pt. To separate significant interferences from ¹⁵N¹⁶O⁺, ¹⁴N¹⁶O¹H⁺, ¹²C¹⁸O¹H⁺, and ¹³C¹⁷O¹H⁺ on ³¹P, high-mass resolution (m/Δm = 4500) proved to be mandatory. The P/Pt signal ratio of 2/1 obtained corresponds to the molar ratio in the bis adduct cis-[Pt(NH₃)₂(GMP)₂]^2–.     

Improving the Stability of Maleimide–Thiol Conjugation for Drug Targeting

Maleimides are essential compounds for drug conjugation reactions via thiols to antibodies, peptides and other targeting units. However, one main drawback is the occurrence of thiol exchange reactions with, for example, glutathione resulting in loss of the targeting ability. A new strategy to overcome such retro-Michael exchange processes of maleimide–thiol conjugates by stabilization of the thiosuccinimide via a transcyclization reaction is presented. This reaction enables the straightforward synthesis of stable maleimide–thiol adducts essential in drug-conjugation applications.     

Janus Gold Nanostars–Mesoporous Silica Nanoparticles for NIR-Light-Triggered Drug Delivery

Janus gold nanostar–mesoporous silica nanoparticle ( AuNSt–MSNP ) nanodevices able to release an entrapped payload upon irradiation with near infrared (NIR) light were prepared and characterized. The AuNSt surface was functionalized with a thiolated photolabile molecule ( 5 ), whereas the mesoporous silica face was loaded with a model drug (doxorubicin) and capped with proton-responsive benzimidazole-β-cyclodextrin supramolecular gatekeepers ( N 1 ). Upon irradiation with NIR-light, the photolabile compound 5 photodissociated, resulting in the formation of succinic acid, which induced the opening of the gatekeeper and cargo delivery. In the overall mechanism, the gold surface acts as a photochemical transducer capable of transforming the NIR-light input into a chemical messenger (succinic acid) that opens the supramolecular nanovalve. The prepared hybrid nanoparticles were non-cytotoxic to HeLa cells, until they were irradiated with a NIR laser, which led to intracellular doxorubicin release and hyperthermia. This induced a remarkable reduction in HeLa cells viability.     

Host–guest interaction of hemicucurbiturils with phenazine hydrochloride salt

The host–guest interactions between phenazine hydrochloride salt (PheH⁺) and hemicucurbit[n]uril (n = 6 or 12) (HemiQ[6 or 12]) have been studied by ¹H NMR, UV–vis, IR, mass spectrometry (MS) and quantum chemistry. In ¹H NMR spectra, the broadening of proton resonances of the hosts suggests the interactions of PheH⁺ with HemiQs. The quantitative stabilities of the host–guest systems have been obtained by UV–vis titration experiments, that is, the stoichiometric interactions of PheH⁺ with HemiQ[6] have been observed with an association constant of K_a = (2.5 ± 1.2) × 10⁶ L mol^? 1, while the 2:1 ratio complexes of PheH⁺ with HemiQ[12] are formed with stepwise association constants of K₁ = (9.2 ± 2.8) × 10⁴ L mol^? 1 and K₂ = (6.4 ± 0.9) × 10⁵ L mol^? 1, respectively, which induce a total association constant of K_a = 5.9 × 10¹⁰ L² mol^? 2. Both the 1:1 and 2:1 complexes have been detected by MS. Quantum chemistry calculations have been used to understand the static structures and thermodynamic stabilities of the supramolecular assemblies.     

Metal–organic interaction probed by First Principles STM simulations

The Review is devoted to recent progress made from the combination of Scanning Tunneling Microscope (STM) experiments and First Principles atomistic simulations in the chemical characterization of metal–organic interfaces. Density Functional Theory (DFT) has now reached the point to mimic in a quantitative way two pillars of the STM probe: the imaging mode convoluting the topographic and electronic properties and the spectroscopy modes comprising of elastic and inelastic detection ways. We present a selection of hybrid interfaces ranging from isolated benzene derivatives to thin honeycomb carbon film – a single graphene layer – deposited onto transition metal surfaces. The direct experimental analysis of these interfaces was error-prone, necessitating the confrontation with First Principles atomistic simulations. The few examples thus illustrate the power of different kinds of STM simulations to complement the STM data, in order to unambiguously identify the chemical structure of organic adsorbates.     

In-vitro drug–drug interaction studies of diltiazem with floroquinolones

Diltiazem is an established cardiovascular drug mainly used for the management of hypertension specifically for the angina pectoris. Fluoroquinolones are widely prescribed against the treatment of severe infections. In vitro relations of diltiazem with fluoroquinolones (ciprofloxacin, levofloxacin, norfloxacin, and ofloxacin) were examined using spectrophotometric and separation techniques, i.e., RP-HPLC. Diltiazem’s availabilities were observed to be predisposed highly in the presence of fluoroquinolones. To investigate the mechanism of interaction in a variety of dissolution environments, i.e., simulating body environments with regard to pH on these interactions has been studied. Moreover, complex of diltiazem–fluoroquinolones were prepared and elucidated through IR spectroscopy and confirmed by computational molecular modeling.