Formation Of Hydrogen Bonding Interactions Research Articles

Screening ionic liquids based on COSMO-SAC model for extracting organic sulfur from coal and mechanism study

Screening suitable ionic liquids（ILs） for removing organic sulfur compounds from coal and discovering new, effective and environmentally friendly coal desulfurization additives is crucial. The solubility properties (SP) of six organic sulfur model compounds (OSMCs) in imidazole ILs were calculated based on the COSMO-SAC model. The results showed that 2-thiophenecarboxylic acid and 2-aminophenyl phenyl sulfone exhibited favorable solubility properties in certain ILs. The solubility properties of partial imidazole ILs consisting of [Cl]- were significantly better than other anions. Through the σ -profiles analysis of ILs anions, cations and OSMCs, it showed that [Cl]- had a higher tendency to be hydrogen bond acceptor than other anions. The polar groups in OSMCs increased the hydrogen bond donor or acceptor sites for interactions with ILs, while extended the optional range of ILs for hydrogen bond interactions with OSMCs. The extraction efficiencies of 2-thiophenecarboxylic acid by ILs were above 25%, with [DMIM][Cl] displaying the highest efficiency at 47.5%. Meanwhile, [DMIM][Cl] was the most effective extractant for removing all OSMCs except benzothiophene, which was basically consistent with the calculation results. Electrostatic potential analysis was used to obtain the sites where OSMCs are the most likely to form hydrogen bond interactions with [DMIM][Cl]. And characterization of hydrogen bond formation between ILs and OSMCs was obtained by FTIR analysis. The hydrogen bond formed by p-thiocresol with [DMIM][Cl] is weak, and the hydrogen bonds formed by 2-thiophenecarboxylic acid, 2-aminophenyl phenyl sulfone with [DMIM][Cl] are relatively strong. The analysis of intermolecular hydrogen bond interactions verified the mechanism underlying the excellent extraction performance for specific OSMCs by the selected ILs.

Density functional theory (DFT), molecular docking, and xanthine oxidase inhibitory studies of dinaphthodiospyrol S from Diospyros kaki L

In this work, we investigated Diospyros kaki extract and an isolated compound for their potential as xanthine oxidase (XO) inhibitors, a target enzyme involved in inflammatory disorders. The prepared extract was subjected to column chromatography, and dinaphthodiospyrol S was isolated. Then XO inhibitory properties were assessed using a spectrophotometry microplate reader. DMSO was taken as a negative control, and allopurinol was used as a standard drug. The molecular docking study of the isolated compound to the XO active site was performed, followed by visualization and protein–ligand interaction. The defatted chloroform extract showed the highest inhibitory effect, followed by the chloroform extract and the isolated compound. The isolated compound exhibited significant inhibitory activity against XO with an IC50 value of 1.09 µM. Molecular docking studies showed that the compound strongly interacts with XO, forming hydrogen bond interactions with Arg149 and Cys113 and H-pi interactions with Cys116 and Leu147. The binding score of −7.678 kcal/mol further supported the potential of the isolated compound as an XO inhibitor. The quantum chemical procedures were used to study the electronic behavior of dinaphthodiospyrol S isolated from D. kaki. Frontier molecular orbital (FMO) analysis was performed to understand the distribution of electronic density, highest occupied molecular orbital HOMO, lowest unoccupied molecular orbital LUMO, and energy gaps. The values of HOMO, LUMO, and energy gap were found to be −6.39, −3.51 and 2.88 eV respectively. The FMO results indicated the intramolecular charge transfer. Moreover, reactivity descriptors were also determined to confirm the stability of the compound. The molecular electrostatic potential (MEP) investigation was done to analyze the electrophilic and nucleophilic sites within a molecule. The oxygen atoms in the compound exhibited negative potential, indicating that they are favorable sites for electrophilic attacks. The results indicate its potential as a therapeutic agent for related disorders. Further studies are needed to investigate this compound's in vivo efficacy and safety as a potential drug candidate.

How Ligands Interact with the Kinase Hinge.

ATP-competitive kinase inhibitors form hydrogen bond interactions with the kinase hinge region at the adenine binding site. Thus, it is crucial to explore hinge-ligand recognition as part of a rational drug design strategy. Here, harnessing known ligand-bound kinase structures and experimental assay resources, we first created a kinase structure-assay database (KSAD) containing 2705 nM ligand-bound kinase complexes. Then, using KSAD, we systematically investigate hinge-ligand binding patterns using interaction fingerprints, thereby delineating 15 different hydrogen-bond interaction modes. We believe these results will be valuable for de novo drug design and/or scaffold hopping of kinase-targeted drugs.

Design of St-2-2 7α-HSDH mutants for altering substrate preference and thermostability

Tauroursodeoxycholic acid (TUDCA) is the main active ingredient in bear bile powder. 7α-hydroxysteroid dehydrogenase (7α-HSDH), which selectively catalyzes the oxidation of taurochenodeoxycholic acid (TCDCA) to produce TUDCA is important when using chicken bile powder as a substrate. St-2-2 is an NADP(H)-dependent 7α-HSDH with higher activity on taurocholic acid (TCA) than on TCDCA. Here, we designed mutants of St-2-2 to alter the substrate preference (from TCA to TCDCA). Interestingly, mutant I255G had 3.38-fold increased catalytic activity toward TCDCA compared with St-2-2 and decreased catalytic activity to 4.6% that of St-2-2 toward TCA. In addition, I255T had higher thermostability. For TCDCA, I255G and I255T had lower KM values (0.07 mM, 0.13 mM), higher kcat values (201.2 s−1, 184.8 s−1), and lower ∆∆G values (-3.80 kJ mol−1, -2.20 kJ mol−1) than those of St-2-2. Increased α-helix content, more interactions between surrounding residues, and lower RMSD values indicated increased thermostability of I255T. Both I255G and I255T had newly formed hydrogen bond interactions between the catalytic center and substrates, suggesting stronger binding to TCDCA thus improving catalytic activity. This is the first report about altering substrate preference, catalytic activity, and thermostability through single-site mutation of 7α-HSDH.

A simple surface engineering to develop the potential of carbon nitride nanosheets in high-performance polymer nanocomposites conducted by first-principles calculations

The incompatible interface between carbon nitride (CN) nanosheets and polymer resin is a huge challenge to develop high-performance polymer/CN nanocomposites. Recently, the complicated surface functionalization methods reported severely hinder the commercial production and practical application of polymer/CN nanocomposites. Herein, conducted by the first-principles calculations, a simple surface engineering is put forward to change the surface characteristic of CN nanosheets by rapidly introducing oxygen atoms with a chemical oxidation method. Presented by the first-principles calculations, it is found that the introduction of oxygen atoms can enhance the adsorption energy between oxygen-doping carbon nitride nanosheets (OCN) and waterborne polyurethane (WPU) resin. As a result, a stronger interfacial interaction and better dispersion state are presented in WPU/OCN nanocomposites, thus laying the foundation for the properties enhancement. Further, effective suppression effects for thermal pyrolysis and fire hazards of WPU resin are demonstrated by OCN nanosheets. As presented by cone calorimeter results, the peak values of heat release rate and total heat release in WPU/OCN-2 are decreased to 806 kW/m2 and 43.3 MJ/m2, significantly less than those of pure WPU (1028 kW/m2 and 55.9 MJ/m2). Meanwhile, more char residue, lower signal intensity of pyrolysis gas, and a prolonged time for signal peak also confirm that the addition of 2.0 wt% OCN nanosheets can hinder the thermal degradation behavior of WPU resin. In addition, the introduction of oxygen atoms promotes the formation of hydrogen bond interactions between OCN nanosheets and WPU matrix, thus enhancing interfacial compatibility and overcoming the re-stack problem. As a result, break strength and elongation at break of WPU/OCN-2 are up to 621% and 24.4 MPa, respectively. The combination of first-principles calculations and surface engineering opens a new approach for designing and developing high-performance polymer nanocomposites.

Design, synthesis, activity and molecular dynamics studies of 1,3,4-thiadiazole derivatives as selective allosteric inhibitors of SHP2 for the treatment of cancer

Overexpression or gene mutation of SHP2 is closely linked with a variety of cancers and has been identified as a crucial anticancer target. In the study, we took SHP2 allosteric inhibitor SHP099 as the lead compound, and 32 1,3,4-thiadiazole derivatives were identified as selective allosteric inhibitors of SHP2. In vitro enzyme activity test showed that some compounds had high inhibition on full length SHP2, and almost no activity on homologous protein SHP1, exhibiting high selectivity. Compound YF704 (4w) had the best inhibition activity, with IC50 value of 0.25 ± 0.02 μM, and also showed strong inhibitory activity on SHP2-E76K and SHP2-E76A, with IC50 values of 6.88 ± 0.69 μM and 1.38 ± 0.12 μM, respectively. CCK8 proliferation test found that multiple compounds would effectively inhibit the proliferation of a variety of cancer cells. Among them, the IC50 values of compound YF704 on MV4-11 and NCI–H358 cells were 3.85 ± 0.34 μM and 12.01 ± 0.62 μM, respectively. Specially, these compounds were sensitive to NCI–H358 cells containing KRASG12C mutation, thus overcoming the problem that SHP099 was insensitive to such cells. Apoptosis experiment showed that compound YF704 would effectively induce apoptosis of MV4-11 cells. Western blot showed that compound YF704 would downregulate the phosphorylation levels of Erk1/2 and Akt in MV4-11 and NCI–H358 cells. Molecular docking study show that compound YF704 would effectively bind to the allosteric region of SHP2 and form hydrogen bond interactions with key residues Thr108, Arg111 and Phe113. Molecular dynamics study further revealed the binding mechanism of SHP2 and compound YF704. In conclusion, we hope to provide potential SHP2 selective inhibitors and provide valuable clues for cancer treatment.

Design, Synthesis, and Antifungal Activities of Novel Pyrazole-4-carboxamide Derivatives Containing an Ether Group as Potential Succinate Dehydrogenase Inhibitors.

A series of novel pyrazole-4-carboxamides bearing an ether group were designed and synthesized on the basis of the structure of commercial succinate dehydrogenase inhibitor (SDHI) fungicide flubeneteram via scaffold hopping and evaluated for their antifungal activities against five fungi. The bioassay results showed that most of the target compounds exhibited excellent in vitro antifungal activity against Rhizoctonia solani and some compounds exerted remarkable antifungal activities against Sclerotinia sclerotiorum, Botrytis cinerea, Fusarium graminearum, and Alternaria alternate. Particularly, compounds 7d and 12b displayed outstanding antifungal activity against R. solani, with an EC50 value of 0.046 μg/mL, far superior to that of boscalid (EC50 = 0.741 μg/mL) and fluxapyroxad (EC50 = 0.103 μg/mL). Meanwhile, compound 12b also presented a broader fungicidal spectrum than other compounds. Moreover, in vivo anti-R. solani results showed that compounds 7d and 12b could significantly inhibit the growth of R. solani in rice leaves with excellent protective and curative efficacies. In addition, the results of the succinate dehydrogenase (SDH) enzymatic inhibition assay showed that compound 7d generated significant SDH inhibition, with an IC50 value of 3.293 μM, which was about 2 times better than that of boscalid (IC50 = 7.507 μM) and fluxapyroxad (IC50 = 5.991 μM). Furthermore, scanning electron microscopy (SEM) analysis indicated that compounds 7d and 12b significantly destroyed the typical structure and morphology of R. solani hyphae. The molecular docking study revealed that compounds 7d and 12b could embed into the binding pocket of SDH and form hydrogen bond interactions with TRP173 and TRY58 at the activity site of SDH, which was in line with fluxapyroxad, indicating that they had a similar mechanism of action. These results demonstrated that compounds 7d and 12b could be promising candidates of SDHI fungicides, which deserved further investigation.

Dual dynamic crosslinking of rubber for enhanced mechanical properties and reconfigurable shape memory behavior

AbstractConstructing dynamic covalent bonds (DCBs) in rubbers provides a promising avenue to resolve the trade‐offs between chemical crosslinking and recyclability. The reinforcement of dynamic covalent networks by nanofilling is widely adopted, which, however, inevitably hinders the exchange reaction of DCBs and network rearrangement due to the restrictions on chain mobility imposed by fillers. To date, the reinforcement of dynamic covalent networks without affecting the dynamic properties remains challenging. In this work, we report a dual dynamic crosslinking strategy by engineering reversible noncovalent bonds into dynamic covalent rubbers to improve mechanical performance and simultaneously maintain desirable malleability and reprocessability. Specifically, dynamic boronic ester‐crosslinked styrene–butadiene rubber is firstly prepared and then modified through triazolinedione (TAD) click reaction. The grafted urazole groups can form hydrogen bond interactions that further aggregate to form clusters and phase‐separation structure in the networks. Due to the reversible nature of hydrogen bonds, they can act in a sacrificial manner to dissipate mechanical energy, leading to a combination of improved strength, modulus and toughness of the networks. More importantly, the hydrogen‐bonded clusters are dissociated at elevated temperatures, enabling the network dynamic properties to be largely preserved. In addition, the dynamic features of the dual crosslinks (hydrogen bonds and boronic esters) endow the TAD‐modified networks with reconfigurable shape memory effect. © 2023 Society of Industrial Chemistry.

Synthesis and in vitro study of pyrimidine-phthalimide hybrids as VEGFR2 inhibitors with antiproliferative activity.

Aim: Thalidomide, a once notorious sedative, is now clinically used as an antitumor agent. We aimed to use it as a lead compound for designing pyrimidine-phthalimide hybrids. Materials & methods: Nucleophilic substitution reaction of thalidomide analog 4 with primary and/or secondary aliphatic amines afforded pyrimidine-phthalimide hybrids 5a-g, 6 and 7a-d. Results & conclusion: Compound 7c showed high antiproliferative activity against four cell lines: HepG-2 (IC50: 7.86±0.5μM), MCF-7 (IC50: 2.77±0.1μM), HCT-116 (IC50: 5.73±0.4μM) and PC-3 (IC50: 8.32±0.5μM), with selective cytotoxicity for WI-38 (IC50: 43.2±2.56μM). 7c arrested MCF-7 cells at S phase of the cell cycle and increased the total apoptotic cells by 50-fold. 7c inhibited VEGFR2 in vitro (IC50: 0.130±0.02μM). 7c was capable of binding at the VEGFR2 binding site, forming hydrogen bond interactions with Asp1046 and Glu885 in a similar way to sorafenib.

Virtual screening and structure–activity relationship study of novel BTK inhibitors in Traditional Chinese Medicine for the treatment of rheumatoid arthritis

Bruton tyrosine kinase (BTK) is a known drug target for the treatment of autoimmune diseases, including rheumatoid arthritis (RA). In this study, a series of 1-amino-1H-imidazole-5-carboxamide derivatives with good inhibitory activity against BTK were selected to explore the structure-activity relationships of these BTK inhibitors (BTKIs). Furthermore, we concentrated on 182 prescriptions of Traditional Chinese Medicine with therapeutic effects on RA. 54 herbs with a frequency of ≥10 were counted to establish a database containing 4027 ingredients for virtual screening. Five compounds with relatively higher docking scores and better absorption, distribution, metabolism, elimination and toxicity (ADMET) parameters were then selected for higher precision docking. The results demonstrated that the potentially active molecules form hydrogen bond interactions with the hinge region residues Met477, Glu475, glycine-rich P-loop residue Val416, Lys430 and DFG motif Asp539. In particular, they also interact with the key residues Thr474 and Cys481 of BTK. The molecular dynamics (MD) results demonstrated that all five compounds above could bind with BTK stably as its cognate ligand in dynamic conditions. This work identified several potential BTKIs using a computer-aided drug design approach and may provide crucial information for developing novel BTKIs. Communicated by Ramaswamy H. Sarma

Platinum(II) Complexes of 3-Hydroxypyridine-2-Carboxaldehyde, N(4)-Methyl and N(4)-Pyrrolidinyl Thiosemicarbazones: Synthesis, Characterization, and Primary Anticancer Screening against HeLa Cells, and Molecular Docking

Background: Thiosemicarbazones are an important class of synthetic organic compounds exhibiting promising biological activities; antiviral, antibacterial, antitubercular, antiprotozoal, antimalarial, antifungal, enzyme inhibitory and antitumor. Different α-(N)-heterocyclic thiosemicarbazones are potent inhibitor of ribonucleotide reductase enzyme that play a critical role in DNA synthesis, moreover some have been found 1000-fold more potent than the clinical drug hydroxyl urea. Objective: Different coordination complexes have been assessed for their efficacy to target MDR and surpass side effects associated with platinum drugs. In this work, we have prepared and investigated the anticancer potential of new platinum compounds of 3- hydroxy-2-formylpyridine thiosemicarbazones. Methods: Novel Pt(II) complexes, were synthesized and characterized by elemental analyses, FT-IR, 1H-NMR, UV-Visible spectroscopy and mass spectrometry. The in vitro anticancer activity of the synthesized compounds against HeLa cells by MTT assay was assessed. Protein-fixed and ligand-flexible Docking studies were carried out using Lamarckian genetic algorithm and Auto dock 4.2 software. Results: The IC50 values of compounds (3) and (4) through MTT screening against HeLa cells were found 107.16 µM and 132.13 µM respectively. The binding energy value for the complex [Pt(HyPyMe)Cl] was -6.49 kcal/mol. While for complex, [Pt(HyPyPyrd)Cl] was found to have a binding energy value of -6.83 kcal/mol. Conclusion: The spectroscopic and analytical data showed the mononuclear structures and square planar geometry of the Pt(II) complexes. The compounds exhibited moderate antineoplastic activity and N(4)-methyl substituted compound exhibited better anticancer activity. [Pt(HyPyMe)Cl] complex forms Hydrogen bond interactions with guanine-6, guanine-7 and thiamne-8. While [Pt(HyPyPyrd)Cl] interacts with guanine-7 and guanine-16 via hydrogen bond interaction.

Design, Synthesis, Docking Studies, Enzyme Inhibitory and Antiplatelet Aggregation Activities of New 1,3-Diphenyl-3-(Phenylthio)Propan-1-One Derivatives as Selective COX-2 Inhibitors.

Cancer is the second leading cause of death worldwide after heart disease. A vast number of studies indicated that selective cyclooxygenase-2 (COX-2) inhibitors could be chemopreventive against different types of cancer because the expression of COX-2 is increased. Therefore, to develop new therapeutics for cancer, the design and synthesis of new COX-2 inhibitors with few side effects seem attractive as anti-cancer agents. Some of the well-known drugs that have been widely used for some time have been removed from the market due to the cardiac side effects they cause, so there is a need to introduce a scaffold that can inhibit COX-2 with high potency and low side effects. This study aimed to introduce a new COX-2 inhibitor structure. A new series of β-aryl-β-mercapto ketones possessing a methylsulfonyl pharmacophore was synthesized and evaluated as selective COX-2 inhibitors. In-vitro COX-1 and COX-2 inhibition effects of these compounds were evaluated, and molecular modeling was examined. Also, the antiplatelet aggregation activity of the synthesized compounds was tested. In-vitro COX-1 and COX-2 inhibition assays indicated that almost all newly synthesized compounds showed selectivity for COX-2 with IC50 values in the 0.07-0.22 μM range and COX-2 selectivity indexes in the 170 to 703.7 range. Among the tested compounds 1-(4-(methylsulfonyl)phenyl)-3-phenyl-3-(phenylthio)propan-1-one (4a), 3-(3,4- dimethoxyphenyl)-1-(4-(methylsulfonyl)phenyl)-3-(phenylthio)propan-1-one (4g) and 3-(4-fluorophenyl)-1-(4-(methyl sulfonyl)phenyl)-3-(phenylthio)propan-1-one (4h) were the most potent COX-2 inhibitors and 3-(3,4- dimethoxyphenyl)-1-(4-(methylsulfonyl)phenyl)-3-(phenylthio)propan-1-one had the highest selectivity index for COX-2 enzyme inhibitory activity. The Anti-platelet aggregation activity results indicated that the compound 1-(4- (methylsulfonyl)phenyl)-3-(phenylthio)-3-(p-tolyl)propan-1-one (4b) possesses the strong anti-platelet activity. Our molecular modeling studies also indicated that the methylsulfonyl pharmacophore group is placed into the adjunct pocket in the COX-2 active site and forms hydrogen bond interactions with NH of Arg513 and NH of His90. In brief, all designed and synthesized compounds showed moderate to good COX-2 inhibitory effects and showed good anti-platelet activity. Therefore, these compounds have the potential for further research into developing anti-cancer agents.

Design, Synthesis, Anti-tubercular and Docking Studies of Novel 2-Furanyl-3-substituted Quinazolin-4-one Derivatives

In this work, the synthesis, characterization and the anti-tubercular activity of novel 2-furanyl-3- substituted quinazolin-4-one derivatives and also predicted their affinity against Mycobacterium tuberculosis enoyl acyl carrier protein reductase were carried out. The targeted compounds were synthesized by the condensation of 2-(furan-2-yl)-4(3H)-1-benzoxazine-4-one with different primary amines. After structural elucidation using spectral data, the compounds were screened for anti-tubercular activity against Mycobacterium tuberculosis H37RV strain. The binding affinity against enoyl acyl carrier protein reductase was predicted using MOE and FITTED docking tools. The synthesized compounds showed a promising anti-tubercular activity in the range from 12.5 to 100 μg/mL. According to MOE docking, the common amino acids in the active site of InhA were found to form hydrogen bonding and hydrophobic interactions with the synthesized quinazolinones. Docking simulations also showed that an aromatic side chain capable of forming hydrogen bond interactions can increase affinity of 2-furanyl quinazolinones to enoyl acyl carrier protein reductase.

Characterization of a novel thermostable alkaline lipase derived from a compost metagenomic library and its potential application in the detergent industry.

Using composted soil samples, a metagenomic library consisting of 36,000 clones was constructed. Then, a novel lipase, Lip54q, which belongs to the VIII family of lipolytic enzymes, was identified from the metagenomic library by functional screening. To explore the enzymatic properties of Lip54q, lip54q was heterologous expressed in Escherichia coli with a high expression level of recombinant protein up to 720 mg/L. The recombinant enzyme showed the highest activity (28,160 U/mg) against a C10 substrate at pH 9.0 and 47°C, and was stable at temperatures ≤50°C and pH 8.0-11.0. Of particular interest, the surfactants, Tween-20, Tween-80 and Tritonx-100, exhibited strong promoting effects on Lip54q activities regardless of whether low concentrations (0.1%) or high concentrations (10%) were used. Application studies of Lip54q using six commercial detergents indicated that the enzyme had strong tolerance and immersion resistance to all six detergents. The results of oil-stain removal experiments suggested that addition of the enzyme to various commercial detergents could significantly improve the abilities of these detergents to remove oil-stains. Furthermore, the results of a molecular docking analysis of Lip54q showed that both the C10 substrate and linoleic acid molecules could form hydrogen bond interactions with the catalytic amino acids, Ser-268, Glu-168, and Asp-192, in the catalytic center of the enzyme, and the hydrogen bond distances were shorter. The electrostatic attraction between the enzyme and the substrate formed by the hydrogen bond with a shorter distance is stronger, which is conducive to the formation of a more stable complex between the enzyme and the substrate, thus increasing the activity of the enzyme to such substrate. These results 1ay a good foundation for application of this enzyme in the detergent industry in the future.

Improving the thermostability of glycosyltransferase YojK by targeting mutagenesis for highly efficient biosynthesis of rebaudioside D

Rebaudioside D (Reb D), as a healthy natural sweetener, has abundant market potential due to the good taste profile, high sweetness and zero calories. Glycosyltransferase YojK from Bacillus subtilis 168 has been identified with the ability to glycosylate Rebaudioside A (Reb A) to produce Reb D, but the poor thermostability still limits its industrial application. Herein, combined with folding energy calculation, structure analysis and consensus analysis, a combinational mutant YojKM1 (S158E/A218H/I241T/G327N/A369K) with a great increase of half-time at 50°C from 2.16 h to 58.64 h was obtained. Moreover, its catalytic activity was also improved with a 1.39-fold increase. Next, its crystal structure was solved and well demonstrated that the newly formed hydrogen bond interactions, salt bridges and the optimization of surface electrostatic charges enhance its thermostability. Last, a fed-batch reaction was established to prepare Reb D with a great yield of 87.70% at high concentration of Reb A at 50°C. Therefore, an efficient and thermostable YojKM1 was developed for the potential industrial production of Reb D.

Screening and Identification of Novel Soluble Epoxide Hydrolase Inhibitors from Corn Gluten Peptides.

The objective of this study was to investigate the soluble epoxide hydrolase (sEH) inhibitory properties of corn gluten peptides. In total, 400 dipeptides and 8000 tripeptides were first virtually screened by molecular docking and 30 potential sEH inhibitory peptides were selected. Among them, WEY, WWY, WYW, YFW, and YFY showed the highest sEH inhibitory activities with IC50 values of 55.41 ± 1.55, 68.80 ± 7.72, 70.66 ± 9.90, 96.00 ± 7.5, and 94.06 ± 12.86 μM, respectively. These five peptides all behaved as mixed-type inhibitors and were predicted to form hydrogen bond interactions mainly with Asp333, a key residue located in the catalytic active site of sEH. Moreover, it was found that the corn gluten hydrolysates of Alcalase, Flavourzyme, pepsin and pancreatin all exhibited high sEH inhibitory activities, with IC50 values of 1.07 ± 0.08, 1.19 ± 0.24, and 1.46 ± 0.31 mg/mL, respectively. In addition, the sEH inhibitory peptides WYW, YFW, and YFY were successfully identified from the corn gluten hydrolysates by Alcalase using nano-LC-MS/MS. This study demonstrated the sEH inhibitory capacity of peptides for the first time and corn gluten might be a promising food protein source for discovering novel natural sEH inhibitory peptides.

3D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Dynamics Simulations for the Identification of Spleen Tyrosine Kinase Inhibitors

Spleen tyrosine kinase (SYK) is an essential mediator of immune cell signaling and has been anticipated as a therapeutic target for autoimmune diseases, notably rheumatoid arthritis, allergic rhinitis, asthma, and cancers. Significant attempts have been undertaken in recent years to develop SYK inhibitors; however, limited success has been achieved due to poor pharmacokinetics and adverse effects of inhibitors. The primary goal of this research was to identify potential inhibitors having high affinity, selectivity based on key molecular interactions, and good drug-like properties than the available inhibitor, fostamatinib. In this study, a 3D-QSAR model was built for SYK based on known inhibitor IC50 values. The best pharmacophore model was then used as a 3D query to screen a drug-like database to retrieve hits with novel chemical scaffolds. The obtained compounds were subjected to binding affinity prediction using the molecular docking approach, and the results were subsequently validated using molecular dynamics (MD) simulations. The simulated compounds were ranked according to binding free energy (ΔG), and the binding affinity was compared with fostamatinib. The binding mode analysis of selected compounds revealed that the hit compounds form hydrogen bond interactions with hinge region residue Ala451, glycine-rich loop residue Lys375, Ser379, and DFG motif Asp512. Identified hits were also observed to form a desirable interaction with Pro455 and Asn457, the rare feature observed in SYK inhibitors. Therefore, we argue that identified hit compounds ZINC98363745, ZINC98365358, ZINC98364133, and ZINC08789982 may help in drug design against SYK.

Rational drug design, synthesis, and in vivo biological activity of new indolyl-imidazolone hybrids as potential and safer non-steroidal anti-inflammatory agents

ObjectivesThe study aimed to synthesize and evaluate the potential anti-inflammatory and analgesic activities of rationally designed hybrid molecules of imidazolone and indole nuclei linked through a methylene bridge. MethodsIndolyl-imidazolone hybrids were synthesized in three simple steps starting from 2-phenyl-1H-indole (1). In the first step, compound 1 was converted to 2-phenyl-1H-indole-3-carbaldehyde (2) using standard conditions of the Vilsmeier Haack reaction. Benzoyl glycine was reacted with 2 (step 2) followed by treatment with aromatic/aliphatic amines (step 3) to furnish the indolyl-imidazolone hybrids. In vivo anti-inflammatory and analgesic activity along with ulcerogenicity of the prepared hybrids were evaluated in experimental animals. Molecular properties and pharmacokinetic profile were also predicted using online computational software. Cyclooxygenase-2 (COX-2) enzyme (PDB: 3pgh) was used for molecular docking studies. Indomethacin and aspirin were used as reference compounds for the comparison purpose. ResultsThe percentage inhibition in edema in rats and reduction in frequency of acetic acid induced writhes in mice indicated that two compounds namely 3-(3-Hydroxpropyl)-2-phenyl-5-[(2-phenyl-1H-indol-3-yl)methylene]-4H-imidazol-4-one (4g) and 3-(2,4-Dinitrophenyl)-2-phenyl-5-[(2-phenyl-1H-indol-3-yl) methylene]- 4H-imidazol-4-one (4b) could be useful in treating pain and inflammatory conditions. Both the hybrid molecules exhibited better biological spectrum than the standard drug indomethacin. Additionally, both the potent compounds were noted to be less ulcerogenic than indomethacin. Pharmacokinetic profile predicted using ADMETsar and SwissADME cheminformatic software indicated compound 4g to be orally bioavailable with high blood brain barrier permeability. However, molecular docking studies revealed that compound 4b binds to COX-2 enzyme more strongly than 4g as indicated by a lower binding energy and formation of hydrogen bond interactions with amino acid residues in the binding pocket. ConclusionsIt could be concluded that hybrid compounds 4b and 4g are promising lead candidates and should be further studied to develop compounds for the treatment of inflammatory conditions.

Hybrid Nafion Membranes of Ionic Hydrogen-Bonded Organic Framework Materials for Proton Conduction and PEMFC Applications.

As the high-power density and environmentally friendly energy resources, proton exchange membrane fuel cells (PEMFCs) have a promising future in portable power generation. Herein, the hybrid Nafion membranes of ionic hydrogen-bonded organic frameworks (iHOFs) for PEMFC applications are demonstrated. By adjusting the position of sulfonic groups on naphthalene disulfonic acid compounds, four iHOFs with different types of hydrogen bonds were synthesized successfully based on 1,1'-diamino-4,4'-bipyridylium and naphthalene disulfonic acid. The formation of hydrogen bond interactions between amino and sulfonate groups provides a rich hydrogen bond network, which makes such iHOFs have high conductivity, and the maximum value is 2.76 × 10-3 S·cm-1 at 100 °C and 98% RH. Besides, composite membrane materials were obtained by mixing Nafion and iHOFs, and the maximum proton conductivity values can achieve 1.13 × 10-2 S·cm-1 for 6%-iHOF-3/Nafion and 2.87 × 10-3 S·cm-1 for 6%-iHOF-4/Nafion membranes at 100 °C under 98% RH. Through the H2/O2 fuel cell performance test by using iHOF/Nafion as the solid electrolyte, the maximum power and current density values of hybrid membranes are 0.36 W·cm-2 and 1.10 A·cm-2 for 6%-iHOF-3/Nafion and 0.42 W·cm-2 and 1.20 A·cm-2 for 6%-iHOF-4/Nafion at 80 °C and 100% RH. This work provides a practicable approach for establishing high-performance proton exchange hybrid membranes by doping high proton-conducting iHOFs into the Nafion matrix.

Small Molecule Inhibition of PDE6D-RAS Interaction Suppresses the Growth of Acute Lymphoblastic Leukemia Cell Lines

Small Molecule Inhibition of PDE6D-RAS Interaction Suppresses the Growth of Acute Lymphoblastic Leukemia Cell Lines