iPP/HDPE blends compatibilized by a polyester: An unconventional concept to valuable products.

Polyolefins are the most widely used plastics accounting for a large fraction of the polymer waste stream. Although reusing polyolefins seems to be a logical choice, their recycling level remains disappointingly low. This is mainly due to the lack of large-scale availability of efficient and inexpensive compatibilizers for mixed polyolefin waste, typically consisting of high-density polyethylene (HDPE) and isotactic polypropylene (iPP) that, despite their similar chemical hydrocarbon structure, are immiscible. Here, we describe an unconventional approach of using polypentadecalactone, a straightforward and simple-to-produce aliphatic polyester, as a compatibilizer for iPP/HDPE blends, especially the brittle iPP-rich ones. The unexpectedly effective compatibilizer transforms brittle iPP/HDPE blends into unexpectedly tough materials that even outperform the reference HDPE and iPP materials. This simple approach creates opportunities for upcycling polymer waste into valuable products.

SOMC grafting of vanadium oxytriisopropoxide (VO(O i Pr)3) on dehydroxylated silica; analysis of surface complexes and thermal restructuring mechanism.

Vanadium oxytriisopropoxide (VO(O i Pr)3), 1, was grafted on highly dehydroxylated silica (SiO2-700: aerosil silica treated at 700 °C under high vacuum) to generate compound 2 following the concepts and methodology of surface organometallic chemistry (SOMC). The resulting compound was analyzed by elemental analysis, FT-IR, 1H, 13C and 51V solid state (SS) NMR, Raman and EPR spectroscopies. The grafting reaction of 1 to generate 2 was found to lead to the formation of a monopodal surface complex [([triple bond, length as m-dash]Si-O-)V(O)(O i Pr)2], 2m, as well as bipodal [([triple bond, length as m-dash]Si-O-)2V(O)(O i Pr)], 2b, formed along with ([triple bond, length as m-dash]Si-O- i Pr) moieties as an effect of the classical rearrangement of 2m with strained siloxane bridges. Upon controlled thermal treatment at 200 °C under high vacuum, 2m and 2b were found to mainly rearrange to tetrahedral VO4 moieties [([triple bond, length as m-dash]Si-O-)3V(O)] (3) with formation of propylene whereas the ([triple bond, length as m-dash]Si-O- i Pr) groups were preserved. The mechanism of the thermal rearrangement of the isopropoxide groups was investigated by a DFT approach revealing the occurrence of a concerted γ-H-transfer and olefin elimination mechanism.

A novel role for pigment genes in the stress response in rainbow trout (Oncorhynchus mykiss).

In many vertebrate species visible melanin-based pigmentation patterns correlate with high stress- and disease-resistance, but proximate mechanisms for this trait association remain enigmatic. Here we show that a missense mutation in a classical pigmentation gene, melanocyte stimulating hormone receptor (MC1R), is strongly associated with distinct differences in steroidogenic melanocortin 2 receptor (MC2R) mRNA expression between high- (HR) and low-responsive (LR) rainbow trout (Oncorhynchus mykiss). We also show experimentally that cortisol implants increase the expression of agouti signaling protein (ASIP) mRNA in skin, likely explaining the association between HR-traits and reduced skin melanin patterning. Molecular dynamics simulations predict that melanocortin 2 receptor accessory protein (MRAP), needed for MC2R function, binds differently to the two MC1R variants. Considering that mRNA for MC2R and the MC1R variants are present in head kidney cells, we hypothesized that MC2R activity is modulated in part by different binding affinities of the MC1R variants for MRAP. Experiments in mammalian cells confirmed that trout MRAP interacts with the two trout MC1R variants and MC2R, but failed to detect regulation of MC2R signaling, possibly due to high constitutive MC1R activity.

CO2 activation through silylimido and silylamido zirconium hydrides supported on N-donor chelating SBA15 surface ligands.

Density functional theory calculations and 2D 1H-13C HETCOR solid state NMR spectroscopy prove that CO2 can be used to probe, by its own reactivity, different types of N-donor surface ligands on SBA15-supported Zr(IV) hydrides: [≡(Si-O-)(≡Si-N=)[Zr]H] and [≡(Si-NH-)(≡Si-X-)[Zr]H2] (X=O or NH). Moreover, [≡(Si­O-)(≡Si-N=)[Zr]H] activates CO2 more efficiently than the other complexes and leads to the formation of a carbimato Zr formate.

Structure-function relationship of a plant NCS1 member--homology modeling and mutagenesis identified residues critical for substrate specificity of PLUTO, a nucleobase transporter from Arabidopsis.

Plastidic uracil salvage is essential for plant growth and development. So far, PLUTO, the plastidic nucleobase transporter from Arabidopsis thaliana is the only known uracil importer at the inner plastidic membrane which represents the permeability barrier of this organelle. We present the first homology model of PLUTO, the sole plant NCS1 member from Arabidopsis based on the crystal structure of the benzyl hydantoin transporter MHP1 from Microbacterium liquefaciens and validated by molecular dynamics simulations. Polar side chains of residues Glu-227 and backbones of Val-145, Gly-147 and Thr-425 are proposed to form the binding site for the three PLUTO substrates uracil, adenine and guanine. Mutational analysis and competition studies identified Glu-227 as an important residue for uracil and to a lesser extent for guanine transport. A differential response in substrate transport was apparent with PLUTO double mutants E227Q G147Q and E227Q T425A, both of which most strongly affected adenine transport, and in V145A G147Q, which markedly affected guanine transport. These differences could be explained by docking studies, showing that uracil and guanine exhibit a similar binding mode whereas adenine binds deep into the catalytic pocket of PLUTO. Furthermore, competition studies confirmed these results. The present study defines the molecular determinants for PLUTO substrate binding and demonstrates key differences in structure-function relations between PLUTO and other NCS1 family members.

Molecular dynamics and QM/MM-based 3D interaction analyses of cyclin-E inhibitors.

Abnormal expression of cyclin-dependent kinase 2 (CDK2)/cyclin-E is detected in colorectal, ovarian, breast and prostate cancers. The study of CDK2 with a bound inhibitor revealed CDK2 as a potential therapeutic target for several proliferative diseases. Several highly selective inhibitors of CDK2 are currently undergoing clinical trials, but possibilities remain for the identification and development of novel and improved inhibitors. For example, in silico targeting of ATP-competitive inhibitors of CDKs is of special interest. A series of 3,5-diaminoindazoles was studied using molecular docking and comparative field analyses. We used post-docking short time molecular dynamics (MD) simulation to account for receptor flexibility. The three types of structures, i.e., the highest energy, lowest energy and the structure most resembling the X-ray structure (three complexes) were identified for all ligands. QM/MM energy calculations were performed using a DFT b3lyp/6-31 g* and MM OPLS-2005 force field. Conceptual DFT properties such as the interaction energy of ligand to protein, global hardness (η), HOMO density, electrostatic potential, and electron density were calculated and related to inhibitory activity. CoMFA and CoMSIA were used to account for steric and electrostatic interactions. The results of this study provide insight into the bioactive conformation, interactions involved, and the effect of different drug fragments over different biological activities.

In silico QSAR studies of anilinoquinolines as EGFR inhibitors.

Members of the epidermal growth factor receptor (EGFR) family of proteins are frequently overactive in solid tumors. A relatively new therapeutic approach to inhibit the kinase activity is the use of ATP-competitive small molecules. In silico techniques were employed to identify the key interactions between inhibitors and their protein receptors. A series of EGFR inhibitory anilinoquinolines was studied within the framework of hologram quantitative structure activity relationship (HQSAR), density functional theory (DFT)-based QSAR, and three-dimensional (3D) QSAR (CoMFA/CoMSIA). The HQSAR analysis implied that substitutions at certain sites on the inhibitors play an important role in EGFR inhibition. DFT-based QSAR results suggested that steric and electronic interactions contributed significantly to the activity. Ligand-based 3D-QSAR and receptor-guided 3D-QSAR analyses such as CoMFA and CoMSIA techniques were carried out, and the results corroborated the previous two approaches. The 3D QSAR models indicated that steric and hydrophobic interactions are dominant, and that substitution patterns are an important factor in determining activity. Molecular docking was helpful in identifying a bioactive conformer as well as a plausible binding mode. The docked geometry-based CoMFA model with steric and electrostatic fields effect gave q(2) = 0.66, r(2) = 0.94 with r(2) (predictive) = 0.72. Similarly, CoMSIA with hydrophobic field gave q(2) = 0.59, r(2) = 0.85 with r(2) (predictive) = 0.63. Bulky groups around site 3 of ring "C", and hydrophilic and bulky groups at position 6 of ring "A" are desirable, with a hydrophobic and electron-donating group at site 7 of ring "A" being helpful. Accordingly, potential EGFR inhibitors may be designed by modification of known inhibitors.

Pharmacophore identification and validation study of CK2 inhibitors using CoMFA/CoMSIA.

Protein kinase CK2, also known as casein kinase-2, has been found to be involved in cell growth, proliferation and suppression of apoptosis, which is related to human cancers. The series of compounds were identified as casein kinase-2 inhibitors and their inhibitory activities are a function of a variation of their structures. The current study deals with the pharmacophore identification and, accordingly, the three-dimensional quantitative structure-activity relationship model development using Pharmacophore Alignment and Scoring Engine. Several hypotheses were developed for the molecular alignments. On the basis of statistical values, the best-fitted model was identified and the same alignment was used for 3D-QSAR using comparative molecular field analysis/comparative molecular similarity index analysis. Both the CoMFA (R(2)(CV) = 0.58, R(2) = 0.82 and r(2)(pred) = 0.62) and the comparative molecular similarity index analysis (R(2)(CV) = 0.74, R(2) = 0.98 and r(2)(pred) = 0.81) gave reasonable results. Besides pharmacophore-based alignment, the maximum common substructure-based alignment was also used for the comparative molecular field analysis and comparative molecular similarity index analysis. The pharmacophore-based alignment was more prominent and it has provided important information for the modelling of potent inhibitors. The overall study implies that a highly positive and bulky group with H-bond donating property is desirable around the nitrogen atom adjacent to the pyrrolidine ring.

In silico quantitative structure-toxicity relationship study of aromatic nitro compounds.

Small molecules often have toxicities that are a function of molecular structural features. Minor variations in structural features can make large difference in such toxicity. Consequently, in silico techniques may be used to correlate such molecular toxicities with their structural features. Relative to nine different sets of aromatic nitro compounds having known observed toxicities against different targets, we developed ligand-based 2D quantitative structure-toxicity relationship models using 20 selected topological descriptors. The topological descriptors have several advantages such as conformational independency, facile and less time-consuming computation to yield good results. Multiple linear regression analysis was used to correlate variations of toxicity with molecular properties. The information index on molecular size, lopping centric index and Kier flexibility index were identified as fundamental descriptors for different kinds of toxicity, and further showed that molecular size, branching and molecular flexibility might be particularly important factors in quantitative structure-toxicity relationship analysis. This study revealed that topological descriptor-guided quantitative structure-toxicity relationship provided a very useful, cost and time-efficient, in silico tool for describing small-molecule toxicities.

DFT-based de novo QSAR of Phenoloxidase Inhibitors.

The phenoloxidase or tyrosinase is a key enzyme in insects, which is responsible for hydroxylation of tyrosine into o-quinones via o-diphenols. A series of benzaldehyde thiosemicarbazone, benzaldehyde and benzoic acid families were taken with their pragmatic pIC(50) values against phenoloxidase from pieris rapae (Lepidoptera) larvae. Density functional theory-based quantitative structure-activity relationship (QSAR) analyses were performed to speculate the key interaction. The most fitted four different QSAR models were identified and discussed. The softness, electrophilicity index, molar refractivity and log P were identified as best descriptors; however, the atomic values of softness and philicity obtained from Fukui function are more significant than global values. The study reveals that electrostatic and steric fields jointly contribute to activity. To gain further insight, the three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses were performed using two molecular field techniques: comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The successful 3D-QSAR models were obtained from CoMFA (q(2)= 0.94, r(2)= 0.99, r(2)(pred)= 0.92) and CoMSIA (q(2)= 0.94, r(2)= 0.98, r(2)(pred)= 0/95). The CoMFA and CoMSIA results indicate that, a bulky and negative group around sulfur atom but a small and positive group around nitrogen atom might have good effects on activity. The ortho and meta positions of ring are favorable for small group. These QSAR models might be helpful to design the novel and potent inhibitors.

Quantitative structure activity relationship (QSAR) study of estrogen derivatives based on descriptors of energy and softness.

Quantum chemical interaction of estrogen derivatives with their receptor has been explored by using Klopman atomic softness. Four series of estrogen derivatives were taken from the literature and the structure of receptor (PDB code 1QKT) was obtained from the protein databank. It is proposed that three Lys, a His, a Tyr and a Cys residues are important for binding. The basic softness values (E(m)(double dagger)) and acidic softness values (E(n)(double dagger)) of all atoms of estrogen derivatives were evaluated. The required parameters for Klopman equation were taken from PM3 results. The highest E(n)(double dagger) values for each molecules and highest E(m)(double dagger) value for each residue were identified and Delta E(nm)(double dagger) has been derived using them. The lowest Delta E(nm)(double dagger) values were used in addition to Q(min) (highest negative charge), Delta H(f)(0) (heat of formation), E(T) (total energy), and E(E) (electronic energy). Multiple linear regression analysis was employed to correlate the variation of relative binding affinity values. The analyses show that Delta E(nm)(double dagger) values in combination with other descriptors provide significant correlation with relative binding affinity values. The result underscores that carbonyl oxygen of the receptor is important for interaction with estrogen derivatives. This model could be utilized to predict the binding affinity of a new compound of this series.