Heterocyclic Substitutions Greatly Improve Affinity and Stability of Folic Acid towards FRα. an In Silico Insight

Folate receptor alpha (FRα) is known as a biological marker for many cancers due to its overexpression in cancerous epithelial tissue. The folic acid (FA) binding affinity to the FRα active site provides a basis for designing more specific targets for FRα. Heterocyclic rings have been shown to interact with many receptors and are important to the metabolism and biological processes within the body. Nineteen FA analogs with substitution with various heterocyclic rings were designed to have higher affinity toward FRα. Molecular docking was used to study the binding affinity of designed analogs compared to FA, methotrexate (MTX), and pemetrexed (PTX). Out of 19 FA analogs, analogs with a tetrazole ring (FOL03) and benzothiophene ring (FOL08) showed the most negative binding energy and were able to interact with ASP81 and SER174 through hydrogen bonds and hydrophobic interactions with amino acids of the active site. Hence, 100 ns molecular dynamics (MD) simulations were carried out for FOL03, FOL08 compared to FA, MTX, and PTX. The root mean square deviation (RMSD) and root mean square fluctuation (RMSF) of FOL03 and FOL08 showed an apparent convergence similar to that of FA, and both of them entered the binding pocket (active site) from the pteridine part, while the glutamic part was stuck at the FRα pocket entrance during the MD simulations. Molecular mechanics Poisson-Boltzmann surface accessible (MM-PBSA) and H-bond analysis revealed that FOL03 and FOL08 created more negative free binding and electrostatic energy compared to FA and PTX, and both formed stronger H-bond interactions with ASP81 than FA with excellent H-bond profiles that led them to become bound tightly in the pocket. In addition, pocket volume calculations showed that the volumes of active site for FOL03 and FOL08 inside the FRα pocket were smaller than the FA–FRα system, indicating strong interactions between the protein active site residues with these new FA analogs compared to FA during the MD simulations.     

Photodecarboxylative addition of carboxylates to phthalimides: a concise access to biologically active 3-(alkyl and aryl)methylene-1H-isoindolin-1-ones

A series of 3-(alkyl and aryl)methyleneisoindolin-1-one derivatives were synthesized in a simple two-step procedure using a recently established photodecarboxylative addition of carboxylates to phthalimides as the key-step. Subsequent acid-catalyzed dehydration and deprotection furnished the desired target compounds with high E-selectivity. The reaction sequence was applied to the synthesis of the known bioactive phenylethylene derivative, AKS-186. Different analogues, including heteroatom-containing isosteres were also synthesized using this approach.     

2-D/3-D finite-element solution of the steady Euler equations for transonic lifting flow by stream vector correction

In this paper we study the validation of the new formulation (potential-stream vector) of the steady Euler equations in 2-D/3-D transonic lifting regime flow. This approach, which is based on the Helmholtz decomposition of a velocity vector field, is designed to extend the potential approximation of Euler equations for severe situations such as high transonic or rotational subsonic flows. Different results computed by a fixed point algorithm on the stream vector correction are shown and discussed by comparing them with those obtained by the full potential approach.     

Selective Permeability of Uranyl Peroxide Nanocages to Different Alkali Ions: Influences from Surface Pores and Hydration Shells

The precise guidance to different ions across the biological channels is essential for many biological processes. An artificial nanopore system will facilitate the study of the ion‐transport mechanism through nanosized channels and offer new views for designing nanodevices. Herein we reveal that a 2.5 nm‐sized, fullerene‐shaped molecular cluster Li_48+mK₁₂(OH)_m[UO₂(O₂)(OH)]_60?(H₂O)_n (m≈20 and n≈310) ( U₆₀ ) shows selective permeability to different alkali ions. The subnanometer pores on the water–ligand‐rich surface of U₆₀ are able to block Rb⁺ and Cs⁺ ions from passing through, while allowing Na⁺ and K⁺ ions, which possess larger hydrated sizes, to enter the interior space of U₆₀ . An interestingly high entropy gain during the binding process between U₆₀ and alkali ions suggests that the hydration shells of Na⁺/K⁺ and U₆₀ are damaged during the interaction. The ion selectivity of U₆₀ is greatly influenced by both the morphologies of the surface nanopores and the dynamics of the hydration shells.     

Antioxidant oligomeric proanthocyanidins from Cistus salvifolius

The purified proanthocyanidin oligomers of Cistus salvifolius herb extract accounted for 78% of the total proanthocyanidins and 73% of the total antioxidant activity of this extract. To elucidate the structure of the oligomer, it was depolymerized by acid catalysis in the presence of phloroglucinol. The structures of the resulting flavan-3-ols and phloroglucinol adducts were determined on the basis of 1D- and reverse 2D-NMR (HSQC, HMBC) experiments of their peracetylated derivatives, MALDI-TOF-MS and CD spectroscopy. These observations resulting from the degradation with phloroglucinol were confirmed by 13C NMR spectroscopy of the oligomer. The mean molecular weight of the higher oligomeric fraction was estimated to be 5-6 flavan-3-ol-units.     

On new iterative method for solving systems of nonlinear equations

Solving systems of nonlinear equations is a relatively complicated problem for which a number of different approaches have been proposed. In this paper, we employ the Homotopy Analysis Method (HAM) to derive a family of iterative methods for solving systems of nonlinear algebraic equations. Our approach yields second and third order iterative methods which are more efficient than their classical counterparts such as Newton’s, Chebychev’s and Halley’s methods.     

Mixed Variational Principles and Robust Finite Element Design of Gradient Plasticity at Finite Strains

The modeling of size effects in elastic-plastic solids, such as the width of shear bands or the grain size dependence in polycrystals, must be based on non-standard theories which incorporate length-scales. This is achieved by models of strain gradient plasticity, incorporating spatial gradients of selected micro-structural fields which describe the evolving dissipative mechanisms. The key aspect of this work is to provide a rigorous incremental variational formulation and mixed finite element design of additive finite gradient plasticity in the logarithmic strain space. We start from a mixed saddle point principle for metric-type plasticity, which is specified for the important model problem of isochoric plasticity with gradient-extended hardening/softening response. To this end, we propose a novel finite element design of the coupled problem incorporating a local-global solution strategy of short- and long-range fields. This includes several new aspects, such as extended Q1P0-type and MINI-type finite elements for gradient plasticity [4]. (© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim)