Protein kinases are key enzymes in many signal transduction pathways, and play a crucial role in cellular proliferation, differentiation, and various cell regulatory processes. However, aberrant function of kinases has been associated with cancers and many other diseases. Consequently, competitive inhibition of the ATP binding site of protein kinases has emerged as an effective means of curing these diseases. Over the past three decades, thousands of protein kinase inhibitors (PKIs) with varying molecular frames have been developed. Large-scale data mining of the Protein Data Bank resulted in a database of 2139 non-redundant high-resolution X-ray crystal structures of PKIs bound to protein kinases. This provided us with a unique opportunity to study molecular determinants for the molecular recognition of PKIs. A chemoinformatic analysis of 2139 PKIs resulted in findings that PKIs are “flat” molecules with high aromatic ring counts and low fractions of sp3 carbon. All but one PKI possessed one or more aromatic rings. More importantly, it was found that the average weighted hydrogen bond count is inversely proportional to the number of aromatic rings. Based on this linear relationship, we put forward the exchange rule of hydrogen bonding interactions and non-bonded π-interactions. Specifically, a loss of binding affinity caused by a decrease in hydrogen bonding interactions is compensated by a gain in binding affinity acquired by an increase in aromatic ring-originated non-bonded interactions (i.e., π–π stacking interactions, CH–π interactions, cation–π interactions, etc.), and vice versa. The very existence of this inverse relationship strongly suggests that both hydrogen bonding and aromatic ring-originated non-bonded interactions are responsible for the molecular recognition of PKIs. As an illustration, two representative PKI–kinase complexes were employed to examine the relative importance of different modes of non-bonded interactions for the molecular recognition of PKIs. For this purpose, two FDA-approved PKI drugs, ibrutinib and lenvatinib, were chosen. The binding pockets of both PKIs were thoroughly examined to identify all non-bonded intermolecular interactions. Subsequently, the strengths of interaction energies between ibrutinib and its interacting residues in tyrosine kinase BTK were quantified by means of the double hybrid DFT method B2PLYP. The resulting energetics for the binding of ibrutinib in tyrosine kinase BTK showed that CH–π interactions and π–π stacking interactions between aromatic rings of the drug and hydrophobic residues in its binding pocket dominate the binding interactions. Thus, this work establishes that, in addition to hydrogen bonding, aromatic rings function as important molecular determinants for the molecular recognition of PKIs. In conclusion, our findings support the following pharmacophore model for ATP-competitive kinase inhibitors: a small molecule features a scaffold of one or more aromatic rings which is linked with one or more hydrophilic functional groups. The former has the structural role of acting as a scaffold and the functional role of participating in aromatic ring-originated non-bonded interactions with multiple hydrophobic regions in the ATP binding pocket of kinases. The latter ensure water solubility and form hydrogen bonds with the hinge region and other hydrophilic residues of the ATP binding pocket.

Poly(2-hydroxyethylmethacrylate)/Naproxen (NPX/pHEMA) and poly (2-hydroxypropyl methacrylate)/Naproxen (NPX/pHPMA) composites with different NPX content were prepared in situ by free radical photopolymerization route. The resulted hybrid materials were characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), scanning Electron microscopy (SEM), and X-ray diffraction (XRD). These composites have been studied as drug carrier systems, in which a comparison of the in vitro release dynamic of NPX between the two drug carrier systems has been conducted. Different factors affecting the performance of the release dynamic of this drug, such as the amount of Naproxen incorporated in the drug carrier system, the pH of the medium and the degree of swelling, have been investigated. The results of the swelling study of pHEMA and pHPMA in different media pHs revealed that the diffusion of water molecules through both polymer samples obeys the Fickian model. The “in vitro” study of the release dynamic of Naproxen from NPX/pHEMA and NPX/pHPMA drug carrier systems revealed that the higher percentage of NPX released was obtained from each polymer carrier in neutral pH medium, and the diffusion of NPX trough these polymer matrices also obeys the Fickian model. It was also found that the less the mass percent of NPX in the composites, the better its release will be. The comparison between the two drug carrier systems revealed that the pHEMA leads to the best performance in the release dynamic of NPX. Regarding Naproxen solubility in water, the results deducted from the “in vitro” study of NPX/pHEMA10 and NPX/pHPMA10 drug carrier systems revealed a very significant improvement in the solubility of NPX in media pH1 (2.33 times, 1.43 times) and 7 (3.32 times, 2.60 times), respectively, compared to those obtained by direct dissolution of Naproxen powder.

Poly(ethylene-co-vinylalcohol) (E-VOH) and carbon nanotube-filled poly (vinyl alcohol-co-ethylene) (E-VOH/CNT) were used as membranes to separate benzene/cyclohexane mixtures by pervaporation technique. To reach this goal, E-VOH and E-VOH/CNT membranes were prepared by solvent casting method and characterized by differential scanning calorimetry (DSC), thermogravimetry analysis (TGA), X-ray diffraction (XRD), and scanning electron microscopy (SEM). The swelling tests were used to study the mass transfer of the benzene/cyclohexane mixture and their pure components. The separation by pervaporation process was carried out at 25 °C in which the effect of CNTs incorporated into E-VOH matrix and the initial concentration of benzene in the feed on the permeate flux, j, and separation factor, β, performance was investigated. The results obtained were very promising, in which the integration of CNTs through E-VOH chains increased the absorption area and raised the flux to 740 g/m2∙h. The separation factor increased to 9.03 and the pervaporation separation reached an index of 5942.2 g/m2∙h for the azeotropic mixture during 3 h of the separation process. In contrast, for the unfilled E-VOH membrane, it was found that these parameters were a rise of 280 g∙m−2∙h−1, separation factor of 12.90 and pervaporation separation index of 3332.0 g/m2∙h, under the same conditions. Likewise, the calculation of the performance of the E-VOH/CNT membrane with regard to that of the unfilled membrane indicated 2.64 for the total flux and 0.70 for the separation factor. It was also revealed that the best compromise of the filled membrane in terms of total cumulative flux and separation factor is obtained for the feed containing the azeotropic mixture.

Summary Tick-borne flaviviruses (TBFVs) can cause life-threatening encephalitis and hemorrhagic fever. To identify virus-host interactions that may be exploited as therapeutic targets, we analyzed the TBFV polyprotein in silico for antiviral protein-binding motifs. We obtained two putative tumor necrosis factor receptor-associated factor 6 (TRAF6)-binding motifs (TBMs) within the protease domain of the viral nonstructural 3 (NS3) protein. Here, we show that TBFV NS3 interacted with TRAF6 during infection and that TRAF6 supports TBFV replication. The proviral role of TRAF6 was not seen with mosquito-borne flaviviruses, consistent with the lack of conserved TBMs. Mutation of the second TBM within NS3 disrupted TRAF6 binding, coincident with reduced abundance of mature, autocatalytically derived form of the NS3 protease and significant virus attenuation in vitro . Our studies reveal insights into how flaviviruses exploit innate immunity for the purpose of viral replication and identify a potential target for therapeutic design.

The Poly(2-chloroquinyl methacrylate-co-2-hydroxyethyl methacrylate) (CQMA-co-HEMA) drug carrier system was prepared with different compositions through a free-radical copolymerization route involving 2-chloroquinyl methacrylate (CQMA) and 2-hydroxyethyl methacrylate) (HEMA) using azobisisobutyronitrile as the initiator. 2-Chloroquinyl methacrylate monomer (CQMA) was synthesized from 2-hydroxychloroquine (HCQ) and methacryloyl chloride by an esterification reaction using triethylenetetramine as the catalyst. The structure of the CQMA and CQMA-co-HEMA copolymers was confirmed by a CHN elementary analysis, Fourier transform infra-red (FTIR) and nuclear magnetic resonance (NMR) analysis. The absence of residual aggregates of HCQ or HCQMA particles in the copolymers prepared was confirmed by a differential scanning calorimeter (DSC) and XR-diffraction (XRD) analyses. The gingival epithelial cancer cell line (Ca9-22) toxicity examined by a lactate dehydrogenase (LDH) assay revealed that the grafting of HCQ onto PHEMA slightly affected (4.2–9.5%) the viability of the polymer carrier. The cell adhesion and growth on the CQMA-co-HEMA drug carrier specimens carried out by the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay revealed the best performance with the specimen containing 3.96 wt% HCQ. The diffusion of HCQ through the polymer matrix obeyed the Fickian model. The solubility of HCQ in different media was improved, in which more than 5.22 times of the solubility of HCQ powder in water was obtained. According to Belzer, the in vitro HCQ dynamic release revealed the best performance with the drug carrier system containing 4.70 wt% CQMA.

A series of poly(vinyl acetate-co-2-hydroxyethylmethacrylate)/acyclovir drug carrier systems (HEMAVAC) containing different acyclovir contents was prepared through bulk free radical polymerization of 2-hydroxyethyl methacrylate with vinyl acetate (VAc) in presence of acyclovir (ACVR) as the drug using a LED lamp in presence of camphorquinone as the photoinitiator. The structure of the drug carrier system was confirmed by FTIR and 1HNMR analysis, and the uniform dispersion of the drug particles in the carrier was proved by DSC and XRD analysis. The study of the physico-chemical properties of the prepared materials, such as the transparency, swelling capacity, wettability and optical refraction, was carried out by UV–visible analysis, a swelling test and measurement of the contact angle and the refractive index, respectively. The elastic modulus and the yield strength of the wet prepared materials were examined by dynamic mechanical analysis. The cytotoxicity of the prepared materials and cell adhesion on these systems were studied by LDH assay and the MTT test, respectively. The results obtained were comparable to those of standard lenses with a transparency of 76.90–89.51%, a swelling capacity of 42.23–81.80% by weight, a wettability of 75.95–89.04 o, a refractive index of 1.4301–1.4526 and a modulus of elasticity of 0.67–1.50 MPa, depending on the ACVR content. It was also shown that these materials exhibit no significant cytotoxicity; on the other hand, they show significant cell adhesion. The in vitro dynamic release of ACVR in water revealed that the HEMAVAC drug carrier can consistently deliver uniformly adequate amounts of ACVR (5.04–36 wt%) over a long period (7 days) in two steps. It was also found that the solubility of ACVR obtained from the release process was improved by 1.4 times that obtained by direct solubility of the drug in powder form at the same temperature.

A series of cerium and iron mixed oxide catalysts were prepared by thermal decomposition of Fe 1.5 PMo 12 O 40 and Ce 1.5 PMo 12 O 40 heteropolyanions mixture. The prepared catalysts have been characterized and tested for the conversion of isobutane in the presence of CO 2 . Characterization by XRD showed that besides Fe 2 O 3 and CeO 2 , a-MoO 3 was the main phase formed after thermal treatment. The effect of the support, the reaction temperature, and the presence of H 2 O in the reactant mixture was investigated. It has been found that the support enhanced both the conversion and isobutene selectivity. As for the reaction temperature and addition of water, it has been found that increasing the temperature increased both the conversion and isobutene selectivity, whereas the presence of water increased the isobutene selectivity but decreased the conversion.

Background: More recently ibuprofen, was used for the indication of the patency of ductus arteriosus closure in preterm infants; this drug is associated similar side effects include cerebral, renal, and mesenteric circulation. Methods: An electronic search was carried out using search terms such as "renal failure", "kidney failure", "renal injury", ibuprofen, "side effects", "adverse effect", complications. The search in MEDLINE and EMBASE through PubMed search engine resulted in 31 articles. These articles were screened for eligibility criteria included studies aimed to assess renal injury caused by ibuprofen use in infants. Results: After exclusion of irrelevant duplicated and review studies, 12 studies were included in this review. Eight studies were randomized control, 3 retrospective evaluation and 1 retrospective cohort study. the effect of the treatment on the renal function there are two outcomes reported either reduction in serum creatinine or incidence of acute renal failure. Incidence of acute renal failure reported in 4 studies. Conclusion: Although renal failure was more common in infants receiving Indomethacin compared to Ibuprofen, oral Ibuprofen was less toxic to the kidneys than intravenous and the serum creatinine levels after treatment did not differ, this is not significant.