In silico design of peptidic inhibitors targeting estrogen receptor alpha dimer interface

Human estrogen receptor alpha (ERα), which acts as a biomarker and as a therapeutic target for breast cancers, is activated by agonist ligands and co-activator proteins. Selective estrogen receptor modulators (SERM) act as antagonists in specific tissues and tamoxifen, a SERM, has served as a drug for decades for ERα-positive breast cancers. However, the ligand-selective and tissue-specific response of ERα biological activity and the resistance to tamoxifen treatment in advanced stages of ERα-positive breast cancers underscores the need to find a ligand-independent inhibitor for ERα. Here we present a ligand-independent approach of inhibiting ERα transactivation targeting its dimerization-a key process of ERα biological activity. Using in silico techniques, we first elucidated the hydrogen bond interactions involved in dimerization and identified three interfacial sequence motifs, where sequence I (DKITD) and sequence II (QQQHQRLAQ) of one monomer form hydrogen bonding with sequence II and sequence I of the second monomer, respectively, and sequence III (LSHIRHMSNK) hydrogen bonds with the same from the second monomer. Studying the structural stability and the binding affinity of the peptides derived from these sequence motifs, we found that an extended and ARG mutated version (LQQQHQQLAQ) of sequence II can act as a suitable template for designing peptidic inhibitors. It provides additional structural stability and interacts more strongly with ERα dimer interface groove formed by helices 9 and 10/11 and prevent ERα dimerization. Our result provides a novel therapeutic designing pipeline for ligand-independent inhibition of ERα.     

Acid Catalyzed Efficient Syntheses of Aryl‐5H‐dibenzo[b,i]xanthene‐5,7,12,14‐(13H)‐tetraones and 3,3‐(Arylmethylene)bis(2‐hydroxynaphthalene‐1,4‐diones) and In Vitro Evaluation of their Antioxidant Activity

A simple and efficient synthesis of aryl‐5H‐dibenzo[b,i]xanthene‐5,7,12,14‐(13H)‐tetraones and 3,3‐(arylmethylene)bis(2‐hydroxynaphthalene‐1,4‐diones) by the condensation of aromatic aldehydes and 2‐hydroxy‐1,4‐naphthoquinone under extremely mild conditions using catalytic amount of H₂SO₄ or in the presence of acidic ionic liquid 1‐butyl‐3‐methylimidazolium hydrogen sulphate, which could be recycled, has been reported. The radical scavenging capacity of the synthesized compounds has been examined towards the stable free radical 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH), and the compounds 2 were found to scavenge DPPH free radical efficiently.     

Effect of Ag nanoparticle addition and ultrasonic treatment on a stable TiO2 nanofluid

Nanoparticles, when homogeneously dispersed in a base fluid, e.g. water, ethylene glycol etc. are commonly known as nanofluids. Nanofluids have gained attention in the scientific community for their enhanced thermal properties. One of the major problems in using nanofluids as a heat transfer medium for commercial applications is that, in most of the closed circuit industrial cooling processes, the cooling fluid has to be replaced after several cycles of cooling operation because of an increased presence of contaminants. If nanofluids were used as a coolant, it would be very hard to separate the nanoparticles from the waste fluid. The present work is aimed at the separation and recycling of nanoparticles from fluid waste by means of quick settling of titanium dioxide nanoparticles using silver nanoparticles along with ultrasonic treatment. It is observed that with increasing silver concentration and time of ultrasonication, the stability of the dispersion decreases. There is a value for both the silver concentration and ultrasonication time above which the settling time decreases drastically.     

Interaction with Al and Zn induces structure formation and aggregation in natively unfolded caseins

Caseins are phosphoproteins that form the principal protein component of milk, their chief function being the transport of inorganic calcium and phosphate to the neonates. The four major members of the casein family are alpha(s1)-, alpha(s2)- (together referred to as alpha(s)-casein), beta- and kappa-casein, each having a characteristic high negative net charge as well as high hydrophobicity and preferring extended conformational states in solution. We have investigated the influence of the polyvalent metal cations Zn(II) and Al(III) on the structure of bovine caseins, using fluorescence and circular dichroic (CD) spectroscopy and light scattering. Changes in Trp and ANS fluorescence parameters (blue shifts of the emission maxima and enhancement of fluorescence intensity) and in the far-UV CD spectra of the caseins caused by the presence of both metals suggest that conformational changes are induced in them by low concentrations (20-40 microM) of the metal cations. These changes lead to formation of solvent-accessible hydrophobic clusters or cavities that, in turn, cause self-association and precipitation of caseins at higher concentration of the metals. These conclusions are supported by increased binding of ThT to the caseins, as well as enhancement of light scattering intensity, observed in presence of Al(III). The chaperonic property of alpha(s)-casein, which enables it to inhibit thermal aggregation of alcohol dehydrogenase, is shown to be partially destroyed by Zn(II)-induced structural alterations, due possibly to loss of flexibility of the natively unfolded casein chains.     

Conformational studies of 3,4-dideoxy furanoid sugar amino acid containing analogs of the receptor binding inhibitor of vasoactive intestinal peptide

Conformational analysis of vasoactive intestinal peptide (VIP) receptor binding inhibitor Leu¹-Met²-Tyr³-Pro⁴-Thr⁵-Tyr⁶-Leu⁷-Lys⁸1 by various NMR techniques and constrained molecular dynamics (MD) simulation studies revealed that the molecule had a turn structure involving its Tyr³-Pro⁴-Thr⁵-Tyr⁶ moiety with intramolecular hydrogen bond between Tyr⁶NH→Tyr³CO. In order to mimic the structure of 1, peptidomimetic analogs 2-4 were synthesized using conformationally constrained scaffolds of 3,4-dideoxy furanoid sugar amino acids (2S,5R)-ddSaa1 5 and its enantiomer (2R,5S)-ddSaa2 6. All these analogs displayed well defined three-dimensional structures akin to that found in 1. Peptides 2 and 3, which differed only in the sugar amino acid stereochemistry, show propensity of structures with identical intramolecular hydrogen bonds between ThrNH→MetCO. A similar structure with a hydrogen bond between TyrNH→MetCO was observed in 4.     

L-shell/subshell ionization of Au,Pb and Bi by low energy proton impact

Proton induced X-ray emission has been used to measureL-subshell and total ionization cross-sections of Au, Pb and Bi in the energy range of 200–350 keV. The ionization cross-sections have been extracted using the X-ray spectra and other quantities like fluorescence yields, transition probabilities, relative widths and Coster-Krönig fraction etc. involved in the process. The results have been compared with the cross-sections measured before and discussed in the light of known theories regarding the ion-atom collisions.     

Direct Numerical Simulation of Head-On Quenching of Statistically Planar Turbulent Premixed Methane-Air Flames Using a Detailed Chemical Mechanism

A three-dimensional compressible Direct Numerical Simulation (DNS) analysis has been carried out for head-on quenching of a statistically planar stoichiometric methane-air flame by an isothermal inert wall. A multi-step chemical mechanism for methane-air combustion is used for the purpose of detailed chemistry DNS. For head-on quenching of stoichiometric methane-air flames, the mass fractions of major reactant species such as methane and oxygen tend to vanish at the wall during flame quenching. The absence of \(\text {OH}\) at the wall gives rise to accumulation of carbon monoxide during flame quenching because \(\text {CO}\) cannot be oxidised anymore. Furthermore, it has been found that low-temperature reactions give rise to accumulation of \(\text {HO}_{2}\) and \(\mathrm {H}_{2}\mathrm {O}_{2}\) at the wall during flame quenching. Moreover, these low temperature reactions are responsible for non-zero heat release rate at the wall during flame-wall interaction. In order to perform an in-depth comparison between simple and detailed chemistry DNS results, a corresponding simulation has been carried out for the same turbulence parameters for a representative single-step Arrhenius type irreversible chemical mechanism. In the corresponding simple chemistry simulation, heat release rate vanishes once the flame reaches a threshold distance from the wall. The distributions of reaction progress variable c and non-dimensional temperature T are found to be identical to each other away from the wall for the simple chemistry simulation but this equality does not hold during head-on quenching. The inequality between c (defined based on \(\text {CH}_{4}\) mass fraction) and T holds both away from and close to the wall for the detailed chemistry simulation but it becomes particularly prominent in the near-wall region. The temporal evolutions of wall heat flux and wall Peclet number (i.e. normalised wall-normal distance of \(T = 0.9\) isosurface) for both simple and detailed chemistry laminar and turbulent cases have been found to be qualitatively similar. However, small differences have been observed in the numerical values of the maximum normalised wall heat flux magnitude \(\left ({\Phi }_{\max } \right )_{\mathrm {L}}\) and the minimum Peclet number \((Pe_{\min })_{\mathrm {L}}\) obtained from simple and detailed chemistry based laminar head-on quenching calculations. Detailed explanations have been provided for the observed differences in behaviours of \(\left ({\Phi }_{\max }\right )_{\mathrm {L}}\) and \((Pe_{\min })_{\mathrm {L}}\). The usual Flame Surface Density (FSD) and scalar dissipation rate (SDR) based reaction rate closures do not adequately predict the mean reaction rate of reaction progress variable in the near-wall region for both simple and detailed chemistry simulations. It has been found that recently proposed FSD and SDR based reaction rate closures based on a-priori DNS analysis of simple chemistry data perform satisfactorily also for the detailed chemistry case both away from and close to the wall without any adjustment to the model parameters.