Formation Of Hydrogen Bonding Interactions Research Articles

Reveal the interaction mechanism of five old drugs targeting VEGFR2 through computational simulations

VEGFR2, vascular endothelial growth factor receptor 2, plays an important role in anti-angiogenesis and is an effective target for inhibiting tumor cell proliferation and metastasis. Many small molecule inhibitors have so far exhibited fine therapeutic effects but do not rule out some adverse reactions. From the perspective of the new use of old drugs, we use a combination of two different docking methods, molecular dynamics simulations and quantum-chemical calculations to acquire potential anti-angiogenesis inhibitors from the library of FDA-approved drugs. We attain five FDA-approved old drugs from Drugbank as potential inhibitors against VEGFR2. Therein, the anti-tumor effects of three compounds, including vilazodone (psychiatric drug), pranlukast and zafirlukast (asthma drugs), have been reported by previous experiments but no anti-tumor data is available for the other two compounds, including antrafenine (analgesic and anti-inflammatory drug) and iloperidone (psychiatric drug). These five compounds exhibit more stable interaction than sorafenib as a market-oriented drug targeting VEGFR2. In parallel, there is a most stable interaction for zafirlukast while a weakest interaction for iloperidone with VEGFR2. We show that these five compounds bind with the hydrophobic cavity of VEGFR2, then forming hydrogen bond interactions with three key residues, Glu-885, Cys-919 and Asp-1046. Lys-868 and Phe-1047 play an important role in stabilizing the interaction conformation. The binding poses of pranlukast and vilazodone are similar to that of sorafenib, whereas antrafenine and zafirlukast act differently from sorafenib, focusing on the direction difference of the respective ring structure. This work may help to develop new and effective anti-angiogenic inhibitors.

Fabrication and properties of thermoplastic starch/montmorillonite composite using dialdehyde starch as a crosslinker

AbstractThe poor mechanical properties and high water solubility of biodegradable thermoplastic starch (TPS) represent the main disadvantages of TPS in many applications. In this work, TPS film was prepared from a water solution of corn starch modified by 5 wt% dialdehyde starch (DAS) as crosslinking agent and 3 wt% montmorillonite (MMT) as reinforcing additive. Interactions occurring in the TPS films were investigated by Fourier transform infrared (FTIR) spectroscopy, Raman spectroscopy, XRD, DSC, dynamic mechanical thermal analysis (DMTA) and TGA. The results obtained fom FTIR spectroscopy and DSC suggest the formation of hydrogen bond interactions between the hydroxyl group of starch, DAS, the MMT layers and glycerol. DMTA indicated that the relaxation of films with DAS and MMT appears in a higher and broader temperature range due to the starch backbone stiffness; the extreme increase in the storage modulus confirmed the suggested interactions. The determination of the weight loss of the films in water indicated a significant increase of the water resistance of TPS due to incorporation of DAS and MMT. Changes in mechanical properties of the films containing DAS and clay were determined, showing a substantial increase in tensile strength from 2.7 to 6.7 MPa, while Young's modulus increased by 15 times for TPS modified with 5% DAS and 3% MMT. Therefore, the outcomes of this study confirmed that DAS is a suitable biomacromolecule crosslinker for starch and can significantly enhance TPS and TPS/MMT properties. © 2019 Society of Chemical Industry

Preparation, structural analysis, morphological investigation and electrical properties of gold nanoparticles filled polyvinyl alcohol/carboxymethyl cellulose blend

Polymer nanocomposite samples have been prepared through the solution casting method utilizing a polymer blend of polyvinyl alcohol and carboxymethyl cellulose (70/30wt.%) as organic host matrix and different concentrations of biosynthesized gold nanoparticles (Au NPs) by the leaf extract of green mint (Mentha Spicata L.) as inorganic nanofiller. The structural, optical and morphological properties of these samples have been through FT-IR, XRD, UV/Vis. and SEM techniques. The FT-IR spectra confirm the blend components are miscible by the formation of Hydrogen bond interaction and show the polymer-nanoparticle interactions. The XRD analyses depict the semicrystalline structure of these samples and the crystallinity degree decrease with increase of Au NPs content within the PVA/CMC structure. The TEM micrograph of biosynthesized Au NPs indicates that shapes of these NPs are spherical NPs and triangular/hexagonal nanoplates with average size range 5–29nm. The alternating electrical conductivity, electrical impedance, complex dielectric permittivity and electric modulus spectra of prepared samples have been investigated at 25°C in the frequency range (0.1Hz–20MHz). Thus, the variations in values of conductivity, dielectric permittivity and relaxation times indicate the feasibility of these materials as flexible nanodielectric of frequency tunable permittivity for radio/audio frequency operating microelectronic/conventional devices.

A facile synthesis of soluble polyimides with high glass transition temperature and excellent mechanical properties due to intermolecular hydrogen bonds

An unsymmetrical heterocyclic diamine monomer containing proton donor (–NH–), 2-(4-aminophenyl)-5-aminobenzimidazole (PABZ), which can form hydrogen bond interactions with carbonyl functional group, was copolymerized with 4,4′-(hexafluoroisopropylidene)diphthalic anhydride (6FDA) and 2,2′-bis(trifluoromethyl)-4,4′-diaminobiphenyl (TFMB) through two-step synthetic methods to obtain a series of homo- and co-polyimide (PI). The corresponding homo- and co-PI both exhibited good solubility in aprotic polar solvents, such as N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N, N-dimethylformamide, pyridine, and dimethyl sulfoxide. In addition, the PI-containing PABZ units showed excellent tensile strength ranging from 83 to 164 MPa, 130–260% higher than 6FDA/TFMB homo-PIa films. These PIs, especially PABZ/6FDA, showed very high glass transition temperatures, 430°C.

Hydrogen Bond Induced Green Solvent Processed High Performance Ternary Organic Solar Cells with Good Tolerance on Film Thickness and Blend Ratios

AbstractFor comprehensive development of organic solar cells (OSCs), some factors such as environmental stability, low cost, insensitive film thickness, component contents tolerance, and green preparation processes are equally crucial to achieve high power conversion efficiencies (PCEs). In this work, a small molecule 3‐(diethylamino)‐7‐imino‐7H‐benzo[4,5]imidazo[1,2‐a]chromeno[3,2‐c]pyridine‐6‐carbonitrile (DIBC), which is commercially available at low cost, is utilized to realize high‐performance ternary OSCs. Demonstrated via Fourier transform infrared and 2D‐1HNMR, DIBC can form hydrogen bond interactions with [6,6]‐phenyl‐C71‐butyric acid methyl ester (PC71BM) in solid films. Further electrostatic potential (ESP) calculations indicate that the hydrogen bond interaction enhances the ESP of PC71BM and accelerates charge transport between donor and acceptor. As a result, poly(4,8‐bis(5‐(2‐ethylhexyl)thiophen‐2‐yl)benzo[1,2‐b;4,5‐b0]dithiophene‐2,6‐diylalt‐(4‐(2‐ethylhexyl)‐3‐fluorothieno[3,4‐b]thiophene‐)‐2‐carboxylate‐2‐6‐diyl (PTB7‐Th):DIBC:PC71BM‐based ternary OSC achieves a maximum efficiency of 12.17%, which is the best result of green solvent processed fullerene OSCs at present. It is noteworthy that the ternary OSCs also show great tolerance to film thickness and blend ratios. These unique properties are attributed to the hydrogen‐bond‐linked DIBC and PC71BM, which modulates molecule distribution and improves film morphology with an interpenetrating network structure. Furthermore, the DIBC containing device also exhibits good thermal and light radiation stability. These results illustrate that intermolecular hydrogen bond interaction has great potential for realizing high‐performance OSCs.

Antioxidant Activity and Neuroprotective Activity of Stilbenoids in Rat Primary Cortex Neurons via the PI3K/Akt Signalling Pathway.

Antioxidant activity and neuroprotective activity of three stilbenoids, namely, trans-4-hydroxystilbene (THS), trans-3,5,4′-trihydroxy-stilbene (resveratrol, RES), and trans-3′,4′,3,5-tetrahydroxy-stilbene (piceatannol, PIC), against β-amyloid (Aβ)-induced neurotoxicity in rat primary cortex neurons were evaluated. THS, RES, and PIC significantly scavenged DPPH• and •OH radicals. All three stilbenoids were able to inhibit Aβ neurotoxicity by decreasing intracellular reactive oxygen species (ROS) via the PI3K/Akt signalling pathway. Specifically, stilbenoids significantly promoted Akt phosphorylation; suppressed Bcl-2/Bax expression; and inhibited caspase-9, caspase-3, and PARP cleavage. Molecular docking between stilbenoids with Akt indicated that stilbenoids could form hydrogen bond interactions with the COOH-terminal region of Akt. Additionally, the neuroprotective activity of stilbenoids correlated with the number and position of hydroxyl groups. The lack of meta-dihydroxyl groups on THS did not affect its neuroprotective activity in comparison with RES, whereas the ortho-dihydroxyl moiety on PIC significantly enhanced neuroprotective activity. These results provide new insights into the correlation between the biological activity and chemical structure of stilbenoids.

Characteristics and molecular determinants of a highly selective and efficient glycyrrhizin-hydrolyzing β-glucuronidase from Staphylococcus pasteuri 3I10.

Glycyrrhizin (GL), the principal sweet-tasting bioactive ingredient of licorice (root of Glycyrrhiza glabra), shows poor oral absorption and gut microbial transformation of GL to glycyrrhetinic acid (GA) plays a major role for its multiple pharmacological effects. Co-administration of GL-hydrolyzing bacteria appears to be a feasible strategy to enhance GA exposure. This study reported a gut bacterial strain Staphylococcus pasteuri 3I10 which exhibited moderate p-nitrophenyl-β-D-glucuronide (PNPG)-hydrolyzing activity but low GL deglucuronidation activity in its crude lysate. The gus gene encoding S. pasteuri 3I10 β-glucuronidase was successfully cloned and overexpressed in Escherichia coli BL21(DE3). The purified β-glucuronidase (SpasGUS) was 71kDa and showed optimal pH and temperature at 6.0 and 50°C, respectively. Comparing to E. coli β-glucuronidase (EcoGUS), SpasGUS displayed lower velocity and affinity to PNPG hydrolysis (Vmax 16.1 ± 0.9 vs 140.0 ± 4.1μmolmin-1mg-1; Km 469.4 ± 73.4 vs 268.0 ± 25.8μM), but could selectively convert GL to GA at much higher efficiency (Vmax 0.41 ± 0.011 vs 0.005 ± 0.002μmolmin-1mg-1; Km 116.9 ± 15.4 vs 53.4 ± 34.8μM). Molecular docking studies suggested SpasGUS formed hydrogen bond interactions with the glucuronic acids at Asn414, Glu415 and Leu450, and Val159, Tyr475, Ala368, and Phe367 provided a hydrophobic environment for enhanced activity. Two special substrate interaction loops near the binding pocket of SpasGUS (loop 1 β-glucuronidase) may account for the selective and efficient bioconversion of GL to GA, predicting thatloop 1 β-glucuronidases show high possibility in processing GL than mini-loop 1 and loop 2 β-glucuronidases. These findings support potential applications of SpasGUS in cleaving GL to facilitate GA production in vivo or in pharmaceutical industry.

Aspirin-inspired acetyl-donating HDACs inhibitors.

Aspirin is one of the oldest drugs for the treatment of inflammation, fever, and pain. It is reported to covalently modify COX-2 enzyme by acetylating a serine amino acid residue. By virtue of aspirin's acetylating potential, we for the first time developed novel acetyl-donating HDAC inhibitors. In this study, we report the design, synthesis, in silico docking study, and biological evaluation of acetyl-donating HDAC inhibitors. The exposure of MDA-MB-231 cells with compound 4c significantly promotes the acetylation of α-tubulin and histone H3, which are substrates of HDAC6 and HDAC1, respectively. In silico docking simulation also indicates that compound 4c tightly binds to the deep substrate-binding pocket of HDAC6 by coordinating the active zinc ion in a bidentate manner and forming hydrogen bond interactions with Ser531 and His573 amino acid residues. In particular, compound 4c (GI50 = 147μM) affords the significant enhancement of anti-proliferative effect on MDA-MB-231 cells, compared with its parent compound 2c (GI50 > 1000μM) and acetyl-donating group deficient compound 6 (GI50 = 554μM). Overall, compound 4c presents a novel strategy for developing acetyl-donating HDAC inhibitors.

Molecular insight on the non-covalent interactions between carbapenems and L,D-transpeptidase 2 from Mycobacterium tuberculosis: ONIOM study.

Tuberculosis remains a dreadful disease that has claimed many human lives worldwide and elimination of the causative agent Mycobacterium tuberculosis alsoremains elusive. Multidrug-resistant TB is rapidly increasing worldwide; therefore, there is an urgent need for improving the current antibiotics and novel drug targets to successfully curb the TB burden. L,D-Transpeptidase 2 is an essential protein in Mtb that is responsible for virulence and growth during the chronic stage of the disease. Both D,D- and L,D-transpeptidases are inhibited concurrently to eradicate the bacterium. It was recently discovered that classic penicillins only inhibit D,D-transpeptidases, while L,D-transpeptidases are blocked by carbapenems. This has contributed to drug resistance and persistence of tuberculosis. Herein, a hybrid two-layered ONIOM (B3LYP/6-31G+(d): AMBER) model was used to extensively investigate the binding interactions of LdtMt2 complexed with four carbapenems (biapenem, imipenem, meropenem, and tebipenem) to ascertain molecular insight of the drug-enzyme complexation event. In the studied complexes, the carbapenems together with catalytic triad active site residues of LdtMt2 (His187, Ser188 and Cys205) were treated at with QM [B3LYP/6-31+G(d)], while the remaining part of the complexes were treated at MM level (AMBER force field). The resulting Gibbs free energy (ΔG), enthalpy (ΔH) and entropy (ΔS) for all complexes showed that the carbapenems exhibit reasonable binding interactions towards LdtMt2. Increasing the number of amino acid residues that form hydrogen bond interactions in the QM layer showed significant impact in binding interaction energy differences and the stabilities of the carbapenems inside the active pocket of LdtMt2. The theoretical binding free energies obtained in this study reflect the same trend of the experimental observations. The electrostatic, hydrogen bonding and Van der Waals interactions between the carbapenems and LdtMt2 were also assessed. To further examine the nature of intermolecular interactions for carbapenem-LdtMt2 complexes, AIM and NBO analysis were performed for the QM region (carbapenems and the active residues of LdtMt2) of the complexes. These analyses revealed that the hydrogen bond interactions and charge transfer from the bonding to anti-bonding orbitalsbetween catalyticresidues of the enzyme and selected ligands enhances the binding and stability of carbapenem-LdtMt2 complexes. The two-layered ONIOM (B3LYP/6-31+G(d): Amber) model was used to evaluate the efficacy of FDA approved carbapenems antibiotics towards LdtMt2.

Hydroxylated Polybrominated Diphenyl Ethers Exert Estrogenic Effects via Non-Genomic G Protein-Coupled Estrogen Receptor Mediated Pathways.

Background:Numerous studies have indicated the estrogenic effects of polybrominated diphenyl ethers (PBDEs) and hydroxylated PBDEs (OH-PBDEs). However, the previous mechanistic studies focused on their estrogenic effects through genomic transcriptional activation of estrogen receptors.Objective:The present study aimed to investigate the estrogenic effects of PBDEs and OH-PBDEs via nongenomic G protein–coupled estrogen receptor (GPER) pathways.Methods:The binding affinities of 12 PBDEs and 18 OH-PBDEs with GPER were determined by a fluorescence competitive binding assay in a human breast cancer cell line (SKBR3). Molecular docking was performed to simulate the interactions. Their activities on GPER pathways were investigated by detecting calcium mobilization and cyclic adenosine monophosphate (cAMP) accumulation in SKBR3 cells. The effects on SKBR3 cell migration were investigated using Boyden chamber and wound-healing assays.Results:Our results showed that 11 of the OH-PBDEs but none of the PBDEs bound to GPER directly. Relative binding affinities ranged from 1.3% to 20.0% compared to . Docking results suggested that the hydroxyl group played an essential role in the binding of OH-PBDEs to GPER by forming hydrogen bond interactions. Most of the OH-PBDEs activated subsequent GPER signaling pathways. Among them, 4ʹ-OH-BDE-049, 5ʹ-OH-BDE-099, and 3ʹ-OH-BDE-154 displayed the highest activity with lowest effective concentrations (LOECs) of . These three OH-PBDEs also promoted SKBR3 cell migration via GPER pathways with LOECs of .Conclusion:OH-PBDEs could bind to GPER, activate the subsequent signaling pathways, and promote SKBR3 cell migration via GPER pathways. OH-PBDEs might exert estrogenic effects by a novel nongenomic mechanism involving the activation of GPER at nanomolar concentrations. https://doi.org/10.1289/EHP2387

Synthesis of Fluorescent Nanoscale Salts/Metal–Organic Frameworks for Live-Cell Imaging

The reaction between disulfonic acid, i.e., 1,5-naphthalenedisulfonic acid (NDS), Cu(NO3)2·3H2O, and variety of ditopic pyridine analogues viz., 9,10-bis((E)-2-(pyridin-4-yl)vinyl)anthracene (B4PVA), 9,10-bis((E)-2-(pyridin-3-yl)vinyl)anthracene (B3PVA), and 3,3′-(peroxybis(methylene))dipyridine (3PBP), resulted in the formation of salts/metal–organic frameworks (MOFs), i.e., [NDS2–·B4PVA2+·S] (FNP 1a), [NDS2–·3PBP2+·MeOH·H2O] (FNP 1b), [Cu·NDS·B4PVA] (FNP 1c), [Cu·NDS·B3PVA] (FNP 1d), and [Cu·NDS·3PBP] (FNP 1e), by the diffusion method where S in FNP 1a is a squeezed solvent molecule. Sulfonates with six oxygen atoms are involved in coordination with metal center and formed hydrogen bond interactions. X-ray structural analysis showed supramolecular architecture of the salts/MOFs where ligands act as a linear linker. The approximate particle size was calculated by powder X-ray diffraction patterns of the compounds using the Debye–Scherrer equation. The morphological characterization of the FNPs were perfo...

QSAR, Docking and Molecular Fragment Replacement Study based on a Conformation- Independent Approach on Trifluorophenyl β-aminoamide derivatives as DPP IV Inhibitors

Background: Inhibition of Dipeptidyl peptidase IV (DPP IV) enzyme is an attractive and appropriate target for the treatment of type 2 diabetes. In order to discover for potent DPP IV inhibitors a chemoinformatics studies were performed on fifty nine trifluorophenyl β-aminoamide derivatives using Sybyl X 2.1.1. Methods: The comparative molecular field analysis (CoMFA), comparative molecular similarity index analysis (CoMSIA) and hologram quantitative structural activity relationship (HQSAR) and docking techniques were selected, validated and optimized by a test set of fifteen compounds in order to design new molecules. Result: The values of cross validated r2 (q2), non cross validated r2 and predicted r2 were for CoMFA (q2=0.854, r2=0.928, pred. r2=0. 932), CoMSIA (q2 =0. 864, r2=0. 924, pred. r2=0.922) and HQSAR (q2=0.826, r2=0.942, pred. r2=0.705), respectively. Conclusion: The structure activity relationship of selected analysis suggested that bulky and electron withdrawing substituents at 2nd and 3rd position of piperazine ring; bulky and electron withdrawing substituent at R position and less bulky and electron donating substituent at 5th position of piperazine ring were favorable for inhibition of DPP IV enzyme. In docking analysis (3W2T pdb) amino group and carbonyl group of compound 44 formed hydrogen bond interactions with Glu 206, Tyr 662 and Arg 125 respectively at active site of DPP IV enzyme. The present work finding may be helpful in the designing and optimization of novel DPP IV inhibitors. Keywords: CoMFA, conformational analysis, diabetes, DPP IV, trifluorophenyl & beta;-aminoamide derivatives.

Photoelectrochemical sensor based on molecularly imprinted film modified hierarchical branched titanium dioxide nanorods for chlorpyrifos detection

A photoelectrochemical (PEC) sensor based on hierarchical branched titanium dioxide nanorods (B-TiO2 NRs) modified with molecularly imprinted polymer (MIP) was constructed for sensitive and efficient detection of chlorpyris (CPF). B-TiO2 NRs were grown directly on fluorine doped tin oxide substrate by the hydrothermal method and employed as matrix for immobilization of MIP. P-aminothiophenol (ATP) and CPF were assembled on the surface of B-TiO2 NRs by formation of hydrogen-bonding interactions through electropolymerization in the MIP preparation process. The MIP was characterized by scanning electron microscopy, and further confirmed by cyclic voltammetry to prove the successful synthesis. In the proposed sensing platform, the photocurrent response is inversely proportional to the CPF concentration because the insulating layer hinders the harvesting of light and electron transfer with increasing of CPF concentration. Moreover, the MIP based B-TiO2 NRs (MIP-B-TiO2 NRs) had an excellent recognition capacity for specific detection CPF over other pesticides. The PEC sensing platform is developed for the detection of CPF in the linear range from 0.01ngmL−1 to 100ngmL−1 with a low detection limit of 7.4pgmL−1. The proposed sensor offered a promising platform for application in detecting pesticide residuals and other environment deleterious chemicals with excellent sensitivity and selectivity, low interference and high stability.

Rrp9 as a Potential Novel Antifungal Target in Candida albicans: Evidences from In Silico Studies

Dicyclomine is a selective muscarinic M1 receptor antagonist in humans. Dicyclomine targets signal transduction genes and inhibits virulence factors in the human pathogen, Candida albicans. Muscarinic acetylcholine receptors are not known to exist in C. albicans. We carried out a search to identify a muscarinic receptor like proteins in C. albicans. A BLAST protein analysis revealed that a C. albicans protein Rrp9 shares 54% identity and 71% similarity with human muscarinic M1 receptor at 24 amino acids overlap. Global alignment between human muscarinic M1 receptor and C. albicans Rrp9 showed 19% identity and 33% similarity at 570 amino acid residues overlap. Our molecular docking study of dicyclomine with C. albicans, Rrp9, Gpr1, Ste2 and Ste3 showed that dicyclomine could bind only with Rrp9 by forming hydrogen bond interactions with VAL386 and ILE313 amino acid residues in the active site region. Dicyclomine bound with human muscarinic receptor M1 by forming hydrogen bond interaction with ARG123 at the active site region. Our study suggests that Rrp9 may be considered as a potential target for dicyclomine in C. albicans.

Keto-polymethines: a versatile class of dyes with outstanding spectroscopic properties for in cellulo and in vivo two-photon microscopy imaging.

The synthesis of keto-heptamethine derivatives has been expanded to various new symmetrical and asymmetrical structures, including an unprecedented di-anionic keto-polymethine. The spectroscopic behavior of these new dyes has been systematically and thoroughly investigated, revealing that the formation of hydrogen bond interactions with protic solvents is responsible for a dramatic enhancement of the fluorescence quantum yield in the far-red spectral region. The existence of these strong hydrogen-bond interactions was further confirmed by molecular dynamics simulations. These bis-dipolar polymethines exhibit large two-photon absorption (TPA) cross-sections (σ2 in GM) in the near-infrared, making them ideal candidates for NIR-to-NIR two-photon microscopy imaging applications. We demonstrate that the molecular engineering of the hydrophilic/hydrophobic balance enables targeting of different cellular components, such as cytoplasm or cell membranes. Addition of appropriate substituents provides the molecule with high-water-solubility, affording efficient two-photon probes for angiography.

Exploring the selectivity of auto-inducer complex with LuxR using molecular docking, mutational studies and molecular dynamics simulations

Bacteria communicate with one another using extracellular signaling molecules called auto-inducers (AHLs), a process termed as quorum sensing. The quorum sensing process allows bacteria to regulate various physiological activities. In this regard, quorum sensing master regulator LuxR from Vibrio harveyi represents an attractive therapeutic target for the development of novel anti-quorum sensing agents. Eventhough the binding of AHL complex with LuxR is evidenced in earlier reports, but their mode of binding is not clearly determined. Therefore, in the present work, molecular docking, in silico mutational studies, molecular dynamics simulations and free energy calculations were performed to understand the selectivity of AHL into the binding site of LuxR. The results revealed that Asn133 and Gln137 residues play a crucial role in recognizing AHL more effectively into the binding site of LuxR with good binding free energy. In addition to that, the carbonyl group presents in the lactone ring and amide group of AHL plays a vital role in the formation of hydrogen bond interactions with the protein. Further, structure based virtual screening was performed using ChemBridge database to screen potent lead molecules against LuxR. 4-benzyl-2-pyrrolidinone and N-[2(1-cyclohexen-1-yl) enthyl]-N'(2-ethoxyphenyl) were selected based on dock score, binding affinity and mode of interactions with the receptor. Furthermore, binding free energy, density functional theory and ADME prediction were performed to rank the lead molecules. Thus, the identified lead molecules can be used for the development of anti-quorum sensing drugs.

Exploring the inhibitory potential of bioactive compound from Luffa acutangula against NF-κB—A molecular docking and dynamics approach

Nuclear factor kappa B (NF-κB) is a transcription factor, plays a crucial role in the regulation of various physiological processes such as differentiation, cell proliferation and apoptosis. It also coordinates the expression of various soluble proinflammatory mediators like cytokines and chemokines. The 1, 8-dihydroxy-4-methylanthracene-9, 10-dione (DHMA) was isolated from Luffa acutangala and its in vitro cytotoxic activity against NCI-H460 cells was reported earlier. It also effectively induces apoptosis through suppressing the expression NF-κB protein. Based on experimental evidence, the binding affinity of compound 1 with NF-κB p50 (monomer) and NF-κB-DNA was investigated using molecular docking and its stability was confirmed through molecular dynamic simulation. The reactivity of the compound was evaluated using density functional theory (DFT) calculation. From the docking results, we noticed that the hydroxyl group of DHMA forms hydrogen bond interactions with polar and negatively charged amino acid Tyr57 and Asp239 and the protein-ligand complex was stabilized through pi-pi stacking with the help of polar amino acid His114, which plays a key role in binding of NF-κB to DNA at a site of DNA-binding region (DBR). The result indicates that the isolated bioactive compound DHMA might have altered the binding affinity between DNA and NF-κB. These findings suggest that potential use of DHMA in cancer chemoprevention and therapeutics.

Polyacrylamide/metakaolinite nanocomposites by in-situ intercalative polymerization

ABSTRACTA series of polyacrylamide (PAM) organoclay nanocomposites were synthesized by in-situ intercalative polymerization using acrylic amide, sodium hydrogen sulfite, and ammonium peroxydisulfate in the presence of various contents of metakaolinite (MK) modified with potassium acetate (KAc). Both x-ray diffraction data and atomic force microscopy images of PAM/MK nanocomposites indicate that the MK was homogeneously dispersed on the nanoscale into the polymer matrix. Infrared and Raman spectroscopy indicated the formation of hydrogen-bonding interactions between PAM and MK and the distortion of the Si–O tetrahedron and Al–O polyhedron in the polymerization process. In addition, DSC results revealed that when the nanocomposites with MK modified with KAc were less than 10%, they have higher decomposition temperature and better thermal stability in comparison with the pure PAM.

Curcumin Analog L48H37 Prevents Lipopolysaccharide-Induced TLR4 Signaling Pathway Activation and Sepsis via Targeting MD2.

Endotoxin-induced acute inflammatory diseases such as sepsis, mediated by excessive production of various proinflammatory cytokines, remain the leading cause of mortality in critically ill patients. Lipopolysaccharide (LPS), the characteristic endotoxin found in the outer membrane of Gram-negative bacteria, can induce the innate immunity system and through the myeloid differentiation protein 2 (MD2) and Toll-like receptor 4 (TLR4) complex, increase the production of inflammatory mediators. Our previous studies have found that a curcumin analog, L48H37 [1-ethyl-3,5-bis(3,4,5-trimethoxybenzylidene)piperidin-4-one], was able to inhibit LPS-induced inflammation, particularly tumor necrosis factor α and interleukin 6 production and gene expression in mouse macrophages. In this study, a series of biochemical experiments demonstrate L48H37 specifically targets MD2 and inhibits the interaction and signaling transduction of LPS-TLR4/MD2. L48H37 binds to the hydrophobic region of MD2 pocket and forms hydrogen bond interactions with Arg(90) and Tyr(102). Subsequently, L48H37 was shown to suppress LPS-induced mitogen-activated protein kinase phosphorylation and nuclear factor κB activation in macrophages; it also dose dependently inhibits the cytokine expression in macrophages and human peripheral blood mononuclear cells stimulated by LPS. In LPS-induced septic mice, both pretreatment and treatment with L48H37 significantly improved survival and protected lung injury. Taken together, this work identified a new MD2 specific inhibitor, L48H37, as a potential candidate in the treatment of sepsis.

Insights into the mechanism of inhibition of CXCR4: identification of Piperidinylethanamine analogs as anti-HIV-1 inhibitors.

The cellular entry of HIV-1 into CD4(+) T cells requires ordered interactions of HIV-1 envelope glycoprotein with C-X-C chemokine receptor type 4 (CXCR4) receptors. However, such interactions, which should be critical for rational structure-based discovery of new CXCR4 inhibitors, remain poorly understood. Here we first determined the effects of amino acid substitutions in CXCR4 on HIV-1NL 4 - 3 glycoprotein-elicited fusion events using site-directed mutagenesis-based fusion assays and identified 11 potentially key amino acid substitutions, including D97A and E288A, which caused >30% reductions in fusion. We subsequently carried out a computational search of a screening library containing ∼604,000 compounds, in order to identify potential CXCR4 inhibitors. The computational search used the shape of IT1t, a known CXCR4 inhibitor, as a reference and employed various algorithms, including shape similarity, isomer generation, and docking against a CXCR4 crystal structure. Sixteen small molecules were identified for biological assays based on their high shape similarity to IT1t, and their putative binding modes formed hydrogen bond interactions with the amino acids identified above. Three compounds with piperidinylethanamine cores showed activity and were resynthesized. One molecule, designated CX6, was shown to significantly inhibit fusion elicited by X4 HIV-1NL 4 - 3 glycoprotein (50% inhibitory concentration [IC50], 1.9 μM), to inhibit Ca(2+) flux elicited by stromal cell-derived factor 1α (SDF-1α) (IC50, 92 nM), and to exert anti-HIV-1 activity (IC50, 1.5 μM). Structural modeling demonstrated that CX6 bound to CXCR4 through hydrogen bond interactions with Asp97 and Glu288. Our study suggests that targeting CXCR4 residues important for fusion elicited by HIV-1 envelope glycoprotein should be a useful and feasible approach to identifying novel CXCR4 inhibitors, and it provides important insights into the mechanism by which small-molecule CXCR4 inhibitors exert their anti-HIV-1 activities.