Investigation of binding mechanism and downregulation of elacestrant for wild and L536S mutant estrogen receptor-α through molecular dynamics simulation and binding free energy analysis

The selective estrogen receptor downregulators (SERDs) are the new emerging class of drugs that are used for the treatment of endocrine resistance breast cancer. Elacestrant (ELA) is a new SERD, currently it is in phase II clinical trial. To understand the ELA–ERα interactions, the molecular docking analysis has been carried out. The ELA molecule binds with the helices H3, H5, H6, and H11 and forms important intermolecular interactions. In addition to this, the tetrahydronapthalene and phenyl rings of ELA are forming T-shaped π···π interactions with the Phe404 and Trp383 residues. Further to understand the stability and flexibility of ELA molecule in the active site of wild and mutated L536S ERα, 100ns molecular dynamics (MD) simulation was performed for both complexes. Interestingly, the MD analysis of wild complex revealed an interaction between ELA and the Asn532 of H11, which is an essential interaction for the downregulation/degradation of ERα, whereas this interaction is not observed in the mutated complex. The drug binding mechanism and H12 dynamics have been elucidated from the analysis of hydrogen bonding interactions and the secondary structure analysis. To explore the binding affinity of ELA molecule, the binding free energy and normal mode analyses were carried out. The per residue decomposition analysis also performed, which shows the contribution of individual amino acids. The principal component analysis and residue interaction network analysis were used to identify the modifications and the interaction between the residues. From the results of different analysis, the inhibition mechanism and downregulation of ERα–ELA complex has been investigated. © 2019 Wiley Periodicals, Inc.     

Rapid Method of Converting Primary Amides to Nitriles and Nitriles to Primary Amides by ZnCl2 using Microwaves under Different Reaction Conditions

A rapid and facile method for the conversion of primary amides to nitriles using inexpensive and readily available ZnCl₂ in aqueous acetonitrile and their regeneration using ZnCl₂–H₂O–THF in the presence of acetamide under microwave irradiation in good yields is reported. The reactions go to completion within a minute.     

Use of Magnesium (Turnings) as a Powerful Catalyst for the O-Acylative Cleavage of Tetrahydrofuran

In a short reaction time, acyl chlorides and dry tetrahydrofuran react in the presence of a catalytic amount of magnesium turnings (Mg) at 25 °C to give 4-chlorobutyl esters in excellent yields.

Exploring the structure,binding mode,flexibility and toxicity nature for Sinefungin molecule: a theoretical approach

Sinefungin (SFN) is an antiviral agent of dengue (DENV) and Zika (ZIKV) viruses with IC₅₀ values of 0.63 and 1.18 µM, respectively. The ADMET properties of SFN revealed that the SFN molecule can be used as an oral drug due to its good solubility nature. The molecular docking analysis of SFN molecule with RNA capping site of DENV and ZIKV NS5 MTase was performed. From this, the SFN-DENV MTase was found to be the best, based on binding energy (??7.56 kcal/mol) and intermolecular interactions. The geometrical parameters of the optimized conformation and docked conformations of SFN molecule are compared which indicated that the intermolecular interactions lead to the modifications of SFN conformation in active site. The molecular electrostatic potential map of SFN depicts the possible nucleophilic and electrophilic locations present in the molecule. The HOMO–LUMO based electronic properties such as electron affinity (A), electrophilicity (ω), electronegativity (χ) and global hardness (η) were calculated to determine the stability and toxicity of SFN molecule. Fukui function and NBO analysis of SFN were also computed.

     

Visible-light-activated selective synthesis of sulfoxides via thiol-ene/oxidation reaction cascade

A convenient, highly selective and metal-free synthesis of sulfoxides from alkenes and thiols using NHPI as an inexpensive and reusable organophotoredox catalyst is reported. The protocol involves radical thiol-ene/oxidation reaction cascade and utilizes visible light and air (O₂) as inexpensive, readily available, non-toxic and eco-sustainable reagents to afford up to 96% yields of the product at room temperature.     

Surface and interfacial structural characterization of MBE grown Si/Ge multilayers

Si/Ge multilayer structures have been grown by solid source molecular beam epitaxy (MBE) on Si (1 1 1) and (1 0 0) substrates and were characterized by high-resolution X-ray diffraction (XRD), atomic force microscopy (AFM), high-depth-resolution secondary ion mass spectroscopy (SIMS) and cross-section high-resolution transmission electron microscopy (HRTEM). A reasonably good agreement has been obtained for layer thickness, interfacial structure and diffusion between SIMS and HRTEM measurements. Epitaxial growth and crystalline nature of the individual layer have been probed using cross-sectional HRTEM and XRD measurements. Surface and interface morphological studies by AFM and HRTEM show island-like growth of both Si and Ge nanostructures.     

Temperature-dependence of time-dependent friction and electric field fluctuations

Molecular-dynamics simulations of a model dipolar system containing two ions have been carried out to study the effect of temperature on the time-dependent friction (ζ(t)) on the solute ions as well as the electric fields in the vicinity of the ions. It is found that with an increase in temperature, (i) the magnitude of ζ (0) increases and (ii) the electric field time correlation functions decay more rapidly at higher temperatures due to faster reorientations and translational diffusion of the molecules. The effects of the size of the system on these properties have also been investigated.     

Development and validation of a liquid chromatographic method for monitoring of process-related synthetic organic impurities of profenofos in technical products

A simple and rapid reversed-phase high-performance liquid chromatographic method for the monitoring of process-related synthetic organic impurities of profenofos (PFS) is developed. Impurities are separated and determined on a reversed-phase Hypersil C(18) column using gradient elution of 50 mM ammonium formate buffer-acetonitrile as a mobile phase and detection at 230 nm at ambient temperature. The method is validated with respect to accuracy, precision, linearity, and limits of detection and quantitation. The method is found to be suitable not only for monitoring the reactions involved in the process development of PFS, but also quality assurance, as it can detect impurities at the level of 1.5 x 10(-8) g.     

Direct synthesis of 6-sulfonylated phenanthridines via silver-catalyzed radical sulfonylation-cyclization of 2-isocyanobiphenyls

A convenient and straightforward synthesis of 6-sulfonylated phenanthridines via silver-catalyzed sequential radical insertion, cyclization and aromatization of 2-isocyanobiphenyls is reported. The protocol does not require a phenanthridine scaffold as a substrate and presents a highly regioselective synthesis of 6-alkyl/arylsulfonyl phenanthridines. The protocol utilizes readily available and easy to handle sodium sulfinates as sulfonating agents and potassium persulfate as an oxidant to afford good to excellent yields of the desired products in a one-pot operation at room temperature.