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Macrocyclic peptides are an important modality in drug discovery, but molecular design is limited due to the complexity of their conformational landscape. To better understand conformational propensities, global strain energies were estimated for 156 protein-macrocyclic peptide cocrystal structures. Unexpectedly large strain energies were observed when the bound-state conformations were modeled with positional restraints. Instead, low-energy conformer ensembles were generated using xGen that fit experimental X-ray electron density maps and gave reasonable strain energy estimates. The ensembles featured significant conformational adjustments while still fitting the electron density as well or better than the original coordinates. Strain estimates suggest the interaction energy in protein-ligand complexes can offset a greater amount of strain for macrocyclic peptides than for small molecules and non-peptidic macrocycles. Across all molecular classes, the approximate upper bound on global strain energies had the same relationship with molecular size, and bound-state ensembles from xGen yielded favorable binding energy estimates.

We report a new method for X-ray density ligand fitting and refinement that is suitable for a wide variety of small-molecule ligands, including macrocycles. The approach (called "xGen") augments a force field energy calculation with an electron density fitting restraint that yields an energy reward during the restrained conformational search. The resulting conformer pools balance goodness-of-fit with ligand strain. Real-space refinement from pre-existing ligand coordinates of 150 macrocycles resulted in occupancy-weighted conformational ensembles that exhibited low strain energy. The xGen ensembles improved upon electron density fit compared with the PDB reference coordinates without making use of atom-specific B-factors. Similarly, on nonmacrocycles, de novo fitting produced occupancy-weighted ensembles of many conformers that were generally better-quality density fits than the deposited primary/alternate conformational pairs. The results suggest ubiquitous low-energy ligand conformational ensembles in X-ray diffraction data and provide an alternative to using B-factors as model parameters.

In the present investigation, the adsorption performance of sesame (Sesamum indicum) oil cake, a waste biomass from the oil extraction industry for remediation of Basic Blue 26 (BB 26) from aqueous media was examined. Effects of pH, adsorbent dosage, BB 26 concentration, shaking time temperature, and ionic strength on BB 26 adsorption have been studied in detail. The residual cake was characterized based on FTIR, zeta potential, SEM-EDAX, and BET techniques. Isotherm and kinetic data have been well-exemplified by Freundlich and pseudo second-order equations, respectively. Maximum uptake capacity was reported to increase significantly from 54.52 mg/g for unmodified cake powder to 91.24 mg/g for ZnCl2-modified cake powder, establishing the importance of ZnCl2 activation. The mechanism of BB 26 adsorption on cake powder was reported to involve different steps as predicted from the fitting of kinetic data to Weber-Morris equation. Thermodynamic studies showed that the process of BB 26 adsorption onto cake powder was accompanied by an increase in entropy and reported to be endothermic and spontaneous. Significant recovery and uptake capacity values were reported from the first to the last cycle of reusability. Due to ease of recovery and regenerability, ZnCl2-modified cake powder has been established as a promising remedy for the successful elimination of BB 26 from aqueous media.

In the present study, tea waste (TW) and cashew nut shell (CNS), waste biomasses are employed in removal of Acid Green 25 dye from aqueous media. Adsorbents are characterized using BET, SEM, zeta potential, and FTIR analyses. BET surface area was obtained as 25.70 and 68.82 m2 g−1 for CNS and TW, respectively. The efficacy of dye removal in the batch study was determined by varying the operating parameters like pH, adsorbent loading, contact time, influent concentration, and temperature. Maximum adsorption was obtained at a pH of 1 using TW and CNS. Adsorbent loading was established at 0.15 g of TW and 0.2 g of CNS. Adsorption was favored at the higher temperatures. Maximum uptake capacities were obtained as 123.46 and 76.34 mg g−1 for TW and CNS, respectively. Better results of dye removal were established for TW in comparison with CNS. Equilibrium data have been well exemplified by Langmuir model, whereas kinetic data suited well to the pseudo-second-order equation for dye removal using TW and CNS. Evaluation of thermodynamic parameters confirmed the spontaneous and physical nature of the studied adsorption. Weber-Morris model established the involvement of different stages in the rate-controlling mechanism. Reusability study performed in five cycles confirmed the potential of TW in removal of Acid Green 25 dye from aqueous media as a slight decrease in uptake capacity from 32.71 mg g−1 for the 1st cycle to 30.52 mg g−1 for the 5th cycle was reported. The overall adsorption study confirmed the efficacy of TW and CNS in removing Acid Green 25 from wastewater.

Using the DUD-E+ benchmark, we explore the impact of using a single protein pocket or ligand for virtual screening compared with using ensembles of alternative pockets, ligands, and sets thereof. For both structure-based and ligand-based approaches, the precise characterization of the binding site in question had a significant impact on screening performance. Using the single original DUD-E protein, Surflex-Dock yielded mean ROC area of 0.81 ± 0.11. Using the cognate ligand instead, with the eSim method for screening, yielded 0.77 ± 0.14. Moving to ensembles of five protein pocket variants increased docking performance to 0.84 ± 0.09. Results for the analogous ligand-based approach (using the five crystallographically aligned cognate ligands) was 0.83 ± 0.11. Using the same ligands, but making use of an automatically generated mutual alignment, yielded mean AUC nearly as good as from single-structure docking: 0.80 ± 0.12. Detailed results and statistical analyses show that structure- and ligand-based methods are complementary and can be fruitfully combined to enhance screening efficiency. A hybrid approach combining ensemble docking with eSim-based screening produced the best and most consistent performance (mean ROC area of 0.89 ± 0.08 and 1% early enrichment of 46-fold). Based on results from both the docking and ligand-similarity approaches, it is clearly unwise to make use of a single arbitrarily chosen protein structure for docking or single ligand query for similarity-based screening.

Pyrazole derivatives were synthesized by bromination of pyrazole, followed by N-alkylation of 4-bromopyrazole. The synthesized derivatives were characterized by microanalytical data and IR and 1H and 13C NMR spectra and were evaluated for their nematicidal activity against the root knot nematode Meloidogyne incognita. The compounds were screened for their egg hatch inhibition and mortality potential, and they showed significant nematicidal activity as compared to the control. 1H-Pyrazol-5(4H)-one was found to be most effective in egg hatch inhibition, and 4-bromopyrazole was found to be most effective in juvenile mortality.

In the present article, a new adsorbent synthesized from Salvadora persica (miswak) powder with chemical activation has been applied to remove Acid Violet 17 dye from aqueous solution. Characterization of the synthesized adsorbent was carried out using the techniques of FTIR, SEM, BET, zeta potential and DLS. The effect of pH, adsorbent dose, contact time, initial dye concentration and temperature were assessed in batch operation. Maximum removal was favored at pH of 2, adsorbent dose of 2 g/L and temperature as 333 K. Chemical activation has increased surface area of raw adsorbent from 58.38 to 124.99 m2/g. Nonlinear regression has been applied for the model fitting of the experimental data. Kinetic data was well described by pseudo-second-order model. Weber-Morris model established involvement of multiple steps in governing the adsorption mechanism. Isotherm data was well described by Freundlich model. Root mean square error analysis was also applied to check the best model fitting. Maximum adsorption capacity values were obtained as 74.28 and 141.30 mg/g for raw adsorbent and activated adsorbent, respectively. Thermodynamic calculations established endothermic and feasible nature of the adsorption. The obtained removal of 97.24 ± 0.69% for simulated solution reduced to 91.17 ± 0.86% in case of real effluent containing 100 mg/L of dye solution as attributed to other compounds present in the actual industrial effluent which can compete on adsorption sites along with the targeted dye. Reusability study performed using ethanol as an eluent confirmed suitability of synthesized adsorbent for dye removal from wastewater. The obtained maximum adsorption capacity along with good reusability results depicted that activated Salvadora persica could be used as an efficient adsorbent for sequestration of Acid Violet 17 from the aqueous phase.

Seven nicotinic acid amides were synthesized by condensation of nicotinic acid adsorbed on silica gel with different aromatic amines. The synthesized compounds were characterized by 1H and 13C NMR and IR spectroscopy and screened for their nematicidal activity against root knot nematode Meloidogyne incognita by egg hatching and mortality test. All compounds exhibited significant nematicidal potential as compared to control. Maximum egg hatching inhibition potential was exhibited by N-(4-bromophenyl)nicotinamide while N-(2,4,5-trichlorophenyl)nicotinamide showed the maximum mortality potential.

The present study aims at evaluating the potential of synthesized biosorbents using NaOH-activated dead leaves of Ficus racemosa (NTFR) and Prunus dulcis (NTPD) for the treatment of real industrial effluents containing dyes. Kinetic and isotherm studies have been performed to establish the important design-related information for the treatment of industrial effluent using synthesized biosorbents. The extent of dye removal obtained as 99.19% for the studies involving pure dye solution of Acid Blue 25 dye with 50 mg L−1 as initial concentration using NTFR biosorbent was found to decrease marginally to 96.72% in the case of real effluent with similar dye loading and under similar operating conditions. Biosorption capacity for the case of pure Acid Blue 25 dye solution obtained as 83.33 mg g−1 also marginally decreased to 80.65 mg g−1 for the industrial effluent. Similarly, for the case of Acid Green 25 dye, extent of dye removal obtained as 92.09% was found to decrease to 84.51% in the case of mixed industrial effluent. In this case, reduction in chemical oxygen demand (COD) was also measured and compared with that of pure Acid Green 25 dye solution. COD reduction was obtained as 53.97% at the optimized dose of 18 g/L of NTPD for mixed industrial effluent which was lower than 92.05% obtained at the optimized biosorbent dose for pure Acid Green 25 dye solution. Langmuir and pseudo-second-order model fitted well to the obtained data in the present study. The obtained results confirmed potential of synthesized biosorbents for removal of dyes from industrial effluent and also established the influence of other compounds present in the industrial effluent on removal rate of individual dyes.

The aim of present study is to improve solubility profile of a poorly soluble anti-cancer natural product, plumbagin at colonic site through incorporation of β-cyclodextrin by preparing complexes by a number of methods. Natural compound plumbagin have lower solubility profile in various GIT medias i.e. 0.1 N HCl, at stomach and intestinal pH. Natural compound plumbagin containing β-cyclodextrin complexes prepared with a number of methods increased the solubility profile in different dissolution media. The nature of plumbagin complexes was ascertained by FTIR spectrum. The tablet formulation of plumbagin β-cyclodextrin complex (kneading method) was prepared and coated with pH sensitive polymer Eudragit L100 for colon targeting. Plumbagin β-cyclodextrin complex can be used in place of pure plumbagin for the preparation of colon targeted drug delivery system.

Constrained, membrane-permeable peptides offer the possibility of engaging challenging intracellular targets. Structure-permeability relationships have been extensively studied in cyclic peptides whose backbones are cyclized from head to tail, like the membrane permeable and orally bioavailable natural product cyclosporine A. In contrast, the physicochemical properties of lariat peptides, which are cyclized from one of the termini onto a side chain, have received little attention. Many lariat peptide natural products exhibit interesting biological activities, and some, such as griselimycin and didemnin B, are membrane permeable and have intracellular targets. To investigate the structure-permeability relationships in the chemical space exemplified by these natural products, we generated a library of scaffolds using stable isotopes to encode stereochemistry and determined the passive membrane permeability of over 1000 novel lariat peptide scaffolds with molecular weights around 1000. Many lariats were surprisingly permeable, comparable to many known orally bioavailable drugs. Passive permeability was strongly dependent on N-methylation, stereochemistry, and ring topology. A variety of structure-permeability trends were observed including a relationship between alternating stereochemistry and high permeability, as well as a set of highly permeable consensus sequences. For the first time, robust structure-permeability relationships are established in synthetic lariat peptides exceeding 1000 compounds.

Introduction Intraperitoneal (IP) Chemotherapy and HIPEC have come to be accepted as standard options in advanced EOC, but are associated with morbidities and treatment delay. This study was done to evaluate the feasibility of administering single dose intraoperative normothermic IP carboplatin in advanced EOC after optimal primary or interval debulking surgery. Methods In a Phase II non randomized prospective study from January 2015 to December 2019, patients of optimally cytoreduced advanced high grade serous ovarian cancer, were administered single dose intraoperative IP carboplatin at room temperature. The immediate ( Results Of 356 patients who underwent surgery for advanced EOC, 86 patients met the inclusion and exclusion criteria. 12 (14%) patients underwent PDS and 74 (86%) IDS. 13 (15.1%) patients underwent laparoscopic/robotic IDS. All patients tolerated IP carboplatin well with no or minimal adverse events. Three cases (3.5%) needed re-suturing for burst abdomen, three cases (3.5%) had paralytic ileus, one case underwent re-exploration for hemorrhage, and one patient died due to due late sepsis. 84 (97.7%) patients received adjuvant IV chemotherapy on time. Conclusion Single dose normothermic intraoperative IP carboplatin is a feasible procedure with no or minimal manageable morbidity. The procedure is user friendly combining the prognostic benefits of IP chemotherapy with assurance of early timely administration of chemotherapy in advanced EOC. Our study is hypothesis generating for future clinical trials comparing single dose NIPEC versus HIPEC in advanced EOC.

AIM: The study aimed to investigate the penetration depth of calcium hydroxide-based root canal sealer into buccolingual and mesiodistal aspects of roots with and without the butterfly effect at coronal and middle root sections. METHODS AND MATERIALS: Twenty single-rooted maxillary premolars were decoronated at the cementoenamel junction and viewed under a light microscope and grouped as Group 1 – butterfly (B) and Group 2 – non-butterfly according to the presence or absence of the effect. Canals were prepared till working length followed with copious irrigation. Canals were finally rinsed with 5 ml of 17% ethylenediaminetetraacetic acid solution and activated using EndoActivator followed by obturation using gutta-percha (warm vertical compaction technique) with Sealapex sealer. To provide fluorescence for confocal laser scanning microscopy (CLSM), the Sealapex was mixed with rhodamine B dye. Root sectioning yielded coronal and middle sections. CLSM was used to assess the penetration of the sealer. STATISTICAL ANALYSIS: Shapiro–Wilk test, unpaired “t-test.” RESULTS: Teeth with the butterfly effect had greater mean penetration buccolingually (905.2 μm) than mesiodistally (182.1 μm; p < 0.001). Coronal sections had greater penetration (517.4 μm) compared with the middle (354.6 μm). CONCLUSION: Sealapex sealer exhibited maximum tubular penetration in teeth with butterfly effect in buccolingual direction at the coronal third level.

Biosorbent synthesized from dead leaves of Prunus Dulcis with chemical activation during the synthesis was applied for the removal of Acid Green 25 dye from wastewater. The obtained biosorbent was characterized using Brunauer-Emmett-Teller analysis, Fourier transform-infrared spectroscopy and scanning electron microscopy measurements. It was demonstrated that alkali treatment during the synthesis significantly increased surface area of biosorbent from 67.205 to 426.346 m2/g. The effect of various operating parameters on dye removal was investigated in batch operation and optimum values of parameters were established as pH of 2, 14 g/L as the dose of natural biosorbent and 6 g/L as the dose of alkali treated biosorbent. Relative error values were determined to check fitting of obtained data to the different kinetic and isotherm models. It was established that pseudo-second order kinetic model and Langmuir isotherm fitted suitably to the obtained batch experimental data. Maximum biosorption capacity values were estimated as 22.68 and 50.79 mg/g for natural biosorbent and for alkali activated Prunus Dulcis, respectively. Adsorption was observed as endothermic and activation energy of 6.22 kJ/mol confirmed physical type of adsorption. Column experiments were also conducted to probe the effectiveness of biosorbent for practical applications in continuous operation. Breakthrough parameters were established by studying the effect of biosorbent height, flow rate of dye solution and initial dye concentration on the extent of dye removal. The maximum biosorption capacity under optimized conditions in the column operation was estimated as 28.57 mg/g. Thomas and Yoon-Nelson models were found to be suitably fitted to obtained column data. Reusability study carried out in batch and continuous column operations confirmed that synthesized biosorbent can be used repeatedly for dye removal from wastewater.

Biosorbents obtained from NaOH and H2SO4 activation of fallen leaves of Ficus racemosa were used for the adsorptive removal of Acid Violet 17 dye from wastewater. BET, SEM and FTIR techniques were used for the characterization of biosorbent. Batch studies were conducted to study the effect of various operating parameters on the extent of adsorption of dye. Maximum dye removal was obtained under optimized conditions of pH as 2 and 3 g/L of biosorbent dose for NaOH activated biosorbent whereas lower extent of removal was obtained for H2SO4 activated biosorbent under similar conditions. The obtained kinetic data were best fitted to pseudo-second order model whereas the adsorption equilibrium data was observed to be in good agreement with Langmuir model. Maximum Langmuir biosorption capacities were estimated to be 45.25, 61.35 and 119.05 mg/g for raw biosorbent, H2SO4 activated biosorbent and NaOH activated biosorbent respectively. The obtained thermodynamic data confirmed that adsorption was endothermic whereas the obtained activation energy as 7.07 kJ/mol confirmed physical nature of the adsorption. Column studies were also performed to establish the practical applicability of the synthesized biosorbent with understanding into effect of biosorbent bed height, initial dye concentration and flow rate. The column data for the equilibrium adsorption was observed to best fit Thomas model. Maximum biosorption capacity obtained in continuous mode under the optimized conditions was 69.08 mg/g. Batch and column desorption studies performed for five cycles established effectiveness and the reusability of synthesized biosorbent to treat industrial dye effluent effectively.

In recent years, there has been a growing fascination towards the development of new antimicrobial agents from various sources to combat microbial resistance. Klebsiella pneumonia and E. coli are the main urinary tract infection (UTI) causing agents. Herein, we report the synthesis and characterization of a novel carbonyl complex of Ru(II) that has been found a good antimicrobial agent against the selected microbes. Hence, may be suggested as potent agent against UTI. The compound on characterization was found octahedral in structure on the basis of comparative DFT-experimental characterization. Molecular specification under B3LYP functional, LANL2DZ basis set for Ru atom and 6-31 g(d,p) for all other atoms were employed. Electron density plots and geometrical optimization were the main theoretical aspects that were invoked. Elemental analysis, mass spectrometry, NMR, FT-IR, UV–Vis and cyclic voltammetry were the physio-chemical techniques at both the experimental and theoretical fronts that helped to establish the proposed structure. From the overall study, it may be remarked that both observed and computed outcomes have been found in good agreement with each other.

Photodynamic therapy (PDT) is a treatment that uses photosensitizing agents to kill cancer cells. Scientific community has been eager for decades to design an efficient PDT drug. Under such purview, the current report deals with the computational photodynamic behavior of ruthenium(II) nitrosyl complex containing N, N'-salicyldehyde-ethylenediimine (SalenH2), the synthesis and X-ray crystallography of which is already known [38] , [39] . Gaussian 09W software package was employed to carry out the density functional (DFT) studies. DFT calculations with Becke-3–Lee–Yang–Parr (B3LYP)/Los Alamos National Laboratory 2 Double Z (LanL2DZ) specified for Ru atom and B3LYP/6-31G(d,p) combination for all other atoms were used using effective core potential method. Both, the ground and excited states of the complex were evolved. Some known photosensitizers were compared with the target complex. Pthalocyanine and porphyrin derivatives were the compounds selected for the respective comparative study. It is suggested that effective photoactivity was found due to the presence of ruthenium core in the model complex. In addition to the evaluation of theoretical aspects in vitro anticancer aspects against COLO-205 human cancer cells have also been carried out with regard to the complex. More emphasis was laid to extrapolate DFT to depict the chemical power of the target compound to release nitric oxide. A promising visible light triggered nitric oxide releasing power of the compound has been inferred. In vitro antiproliferative studies of [RuCl3(PPh3)3] and [Ru(NO)(Salen)(Cl)] have revealed the model complex as an excellent anticancer agent. From IC50 values of 40.031 mg/mL in former and of 9.74 mg/mL in latter, it is established that latter bears more anticancer potentiality. From overall study the DFT based structural elucidation and the efficiency of NO, Ru and Salen co-ligands has shown promising drug delivery property and a good candidacy for both chemotherapy as well as light therapy.

Sugar–metal ion interaction is involved in many biological phenomena. In the evident interests towards Zn(II) compounds and motivated to extrapolate the search for more persuasive zinc compounds to emerge the ability of sugars towards metallotherapy, a systematic hyphenated DFT-experimental study of a novel sugar Schiff base Zn(II) complex of N-dehydroacetic acid-glucosamine (dha-glsH2) is presented. In addition to its formulation based on various spectroscopic and spectrometric techniques, superoxide dismutation of the title complex is also the active goal of the work. A suitable distorted square planar geometry was revealed and the study stems a well promising biological efficiency of target compounds.

Solution processed hybrid organic-inorganic halide perovskite materials have drawn huge attention in recent years. It attracts due to their potential application in 4 th generation of photovoltaic solar cells, light emitting diodes, photo-detectors, laser and related optoelectronic devices. Most commonly, methylammonium lead halide perovskite [CH 3 NH 3 PbX 3 , X = Cl, Br or I] has chemical formula ABX 3 pattern, where A and B represents two cations of dissimilar sizes while X an anion. In the present work, we have successfully synthesized CH 3 NH 3 PbI 3 hybrid organic-inorganic halide perovskite materials with low temperature solution cost method. XRD diffraction was employed to elucidate the structure of prepared perovskite and the crystalline size also estimated from the full width at half maximum (FWHM). The sharper and more symmetric XRD peaks of perovskite sample indicate a better crystallinity of grains with fewer defects. UV-Visible spectroscopy shows the high absorbance in perovskite between wavelengths 400–800nm. Typical sharp PL peak centered at ≈790nm, corresponding to the excitation wavelength of 410nm. We predict that this study will encourage the research on novel near-infrared perovskite materials for optical devices.

A novel biosorbent synthesized from Ficus racemosa leaves based on the treatment using NaOH was applied for removal of Acid Blue 25 from aqueous solution. The synthesized biosorbent was characterized using scanning electron microscopy, Fourier transform infrared spectroscopy and Brunauer–Emmett–Teller analysis. NaOH treatment was demonstrated to remove lignin content from the biomass and to induce the development of significant pores. Batch experiments were performed to evaluate the effect of important operating parameters such as pH (range of 2–10), biosorbent dose (range of 1–10 g/L), contact time (range of 0–5 h), initial dye concentration (range of 50–400 mg/L) and temperature (range of 293–323 K) on the extent of removal of Acid Blue 25. The established optimum conditions were pH of 2, biosorbent dose of 4 g/L, contact time of 3 h and temperature of 323 K, yielding maximum removal of dye. Pseudo-second-order model was found to best fit the kinetic data. Langmuir and Temkin isotherm models were found to best fit the equilibrium data. The obtained thermodynamic parameters confirmed endothermic and spontaneous nature of adsorption. The study established the utility of novel biosorbent for removal of Acid Blue 25 with higher adsorption capacities (83.33 mg/g) as compared to the more commonly used adsorbents. Desorption-adsorption studies conducted for seven cycles indicated potential reusability of synthesized biosorbent for the treatment of dye effluents.

The present paper reports the synthesis and characterization of some new sulfa drug based Schiff base oxovanadium(IV) complexes of composition, [VO(sal-sdz)2(H2O)]·H2O, [VO(sal-sgn)2(H2O)]·H2O, [VO(sal-snm)(H2O)]·H2O, [VO(sal-smr)2(H2O)]·H2O and [VO(dadps)(H2O)]2·2H2O, where sal-sdzH = N-(salicylidene)sulfadizine, sal-sgnH = N-(salicylidene)sulfaguanidine, sal-snmH = N-(salicylidene)sulfanilamide, sal-smrH = N-(salicylidene)sulfamerizine, sal-dadpsH2 = N,N′-bis(salicylidene)-4,4′-diaminodiphenylsulfone, respectively. Complexes, (1)–(4) were prepared by the reaction of VOSO4·5H2O with the Schiff bases in 1:2 metal-ligand ratio while complex (5) in 2:2 metal-ligand ratio in DMF-ethanol medium. The compounds so obtained were characterized by different physico-chemical studies, such as, elemental analysis, molar conductance and magnetic measurements, infrared, ESR, thermogravimetric studies, mass and electronic spectral studies. The overall IR studies conclude that the ligand in complex (1)–(4) behave as monobasic bidentate ON donor, while the ligand in the complex (5) behaves as dibasic tetradentate O2N2 donor. The 3D-molecular modeling and analysis for bond lengths and bond angles have also been carried out for two representative compounds, [VO(sal-snm)2(H2O)]·H2O (3) and [VO(dadps)(H2O)]2·2H2O (5) to substantiate the proposed structures. Based on these studies suitable octahedral structures have been proposed for these complexes.

The uptake and accumulation of polycyclic aromatic hydrocarbons (PAHs) in crops have gained much attention due to their toxicity to humans. Nitrogen (N) is an essential element for plant growth and has also been implicated in the acquisition and acropetal translocation of PAHs. OsNRT2.3b encodes a nitrate (NO3−) transporter that is involved in the acquisition and mobilization of N in rice. Here, we investigated whether overexpression of OsNRT2.3b would exert any mitigating influence on the uptake and translocation of phenanthrene (Phe, a model PAH) in transgenic rice (Oryza sativa). The wild-type seedlings exhibited a reduction in plant height, primary root length, and shoot biomass when grown hydroponically in a medium supplemented with Phe. Acquisition of Phe by the roots and its subsequent translocation to shoots increased concomitantly with an increase in Phe concentration in the medium and duration of the treatment. OsNRT2.3b-overexpressing lines (Ox-6 and Ox-8) were generated independently. Compared with the wild-type, the concentration of Phe in Ox-6 and Ox-8 were significantly lower in the roots (47%–54%) and shoots (22%–31%) grown hydroponically with Phe (1 mg/L). Further, the wild-type and Ox lines were grown to maturity in a pot soil under Phe conditions and the concentrations of Phe and total N were assayed in the culms and flag leaves. Compared with the wild-type, in Ox lines the concentration of total N significantly increased in the culms (288%–366%) and flag leaves (12%–25%), while that of Phe significantly reduced in the culms (25%–28%) and flag leaves (18%–21%). The results revealed an antagonistic correlation between the concentration of total N and Phe. The concentration of Phe was also significantly lower (29%–38%) in the seeds of Ox lines than the wild-type. The study highlighted the efficacy of overexpressing OsNRT2.3b in mitigating the Phe toxicity by attenuating its acquisition, mobilization, and allocation to the seeds.

The present report pertains to synthesis and combined experimental-DFT studies of a series of four novel mixed-ligand complexes of cobalt(II) of the general composition [Co(dha)(L)(H 2 O) 2 ], where dhaH = dehydroacetic acid, LH = β-ketoenolates viz. , o -acetoacetotoluidide ( o -aatdH), o -acetoacetanisidide ( o -aansH), acetylacetone (acacH) or 1-benzoylacetone (1- bac ). The resulting complexes were formulated based on elemental analysis, molar conductance, magnetic measurements, mass spectrometric, IR, electronic, electron spin resonance and cyclic voltammetric studies. The TGA based thermal behavior of one representative complex was evaluated. Molecular geometry optimizations and vibrational frequency calculations have been performed with Gaussian 09 software package by using density functional theory (DFT) methods with B3LYP/LANL2MB combination for dhaH and one of its complexes, [Co(dha)(1- bac )(H 2 O) 2 ]. Theoretical data has been found in an excellent agreement with the experimental results. Based on experimental and theoretical data, suitable trans -octahedral structure has been proposed for the present class of complexes. Moreover, the complexes also showed a satisfactory antibacterial activity.

In the present article, adsorption of anionic dye (Acid Blue 25) using waste tea residue (WTR) was investigated in batch and continuous operation. Clear insight of functional groups, surface charge, morphology, composition, surface area and particle size of WTR was obtained by the characterization techniques of FTIR, zeta potential, SEM-EDX, BET, and DLS analysis. Influence of operating pH, adsorbent loading, influent concentration, contact duration of adsorption and temperature on dye remediation was investigated in batch studies. Evaluated kinetic data was in better agreement with pseudo 2nd order model whereas equilibrium data was in better agreement with Redlich Peterson model. Multiple steps were found to control the mechanism of the studied adsorption. Maximum dye uptake was obtained as 127.14 mg g−1 at optimized pH of 1, loading of 3.5 g L −1 and higher temperature as 318 K. Adsorption process was found to be spontaneous, physical and favored with the rise in temperature. Reusability of WTR in multiple cycles showed a slight drop in dye uptake from 27.95 ± 0.26 mg g−1 at 1st cycle to 26.24 ± 0.21 mg g−1 at 3rd cycle. Continuous studied were also conducted in packed column and influence of column operating parameters as packing height (3–6 cm), concentration (50–200 mg L−1) and the flow rate of influent (5–9 mL min−1) on the efficacy of dye remediation were investigated. Thomas model was reported to be in better agreement with the evaluated breakthrough data. Maximum uptake in continuous studies was reported as 50.82 mg g−1. The obtained results of batch and continuous studies depicted that WTR could be used effectively for remediation of targeted anionic dye from the aqueous phase.

The present investigation assessed the applicability of incense stick ash, a novel and sustainable adsorbent for remediation of Victoria Blue dye from wastewater. Incense stick ash, without any physical and chemical treatment has been applied to investigate the influence of various experimental parameters as pH, loading of adsorbent, concentration, shaking time, temperature and ionic strength on Victoria Blue remediation in a batch operation. Incense stick ash was characterized using BET, DLS, SEM-EDS, FTIR and XRD techniques. BET surface area, pore volume and pore diameter of incense stick ash are obtained as 2.245 m2 g−1, 0.0118 cm3 g−1 and 21.02 nm, respectively. Average particle size of the adsorbent is obtained as 293.2 nm. Goodness of the fit of isotherm and kinetic model to the reported data was identified based on chi squared and coefficient of determination values. Isotherm and kinetic behavior was best represented by Freundlich and pseudo 2nd order equation, respectively. Boyd model confirmed involvement of film diffusion mechanism along with intra-particle for adsorption of Victoria Blue on incense stick ash. Maximum dye uptake was reported as 105.57 mg g−1. Thermodynamic study revealed spontaneous and favorable adsorption of Victoria Blue on incense stick ash at higher temperature. The performed elution and subsequent regeneration study implied desorption capability of incense stick ash and its applicability as a fresh adsorbent for further cycle of adsorption. The overall study implied scavenging potential of incense stick ash, a novel and sustainable adsorbent available at zero cost towards Victoria Blue removal.

In phosphate (Pi)-deprived Arabidopsis (Arabidopsis thaliana), phosphatidylglycerol (PG) is substituted by sulfolipid for maintaining Pi homeostasis. Sulfoquinovosyl diacylglycerol1 (AtSQD1) encodes a protein, which catalyzes uridine diphosphate glucose (UDPG) and sulfite (SO3 2- ) to UDP-sulfoquinovose, which is a key component in the sulfolipid biosynthetic pathway. In this study, a reverse genetics approach was employed to decipher the function of the AtSQD1 homolog OsSQD1 in rice. Differential expressions of OsSQD1 in different tissue and response to -P and -S also detected, respectively. The in vitro protein assay and analysis suggests that OsSQD1 is a UDP-sulfoquinovose synthase. Transient expression analysis showed that OsSQD1 is located in the chloroplast. The analyses of the knockout (ossqd1) and knockdown (Ri1 and Ri2) mutants demonstrated reductions in Pi and total P concentrations, 32 Pi uptake rate, expression levels of Pi transporters and altered developmental responses of root traits, which were accentuated during Pi deficiency. The inhibitory effects of the OsSQD1 mutation were also evident in the development of reproductive tissue. Furthermore, OsSQD1 differently affects lipid composition under different Pi regime affects sulfur (S) homeostasis. Together, the study revealed that OsSQD1 affects Pi and S homeostasis, and lipid composition in response to Pi deprivation.

© 2014 The Author(s). We have previously validated a probabilistic framework that combined computational approaches for predicting the biological activities of small molecule drugs. Molecule comparison methods included molecular structural similarity metrics and similarity computed from lexical analysis of text in drug package inserts. Here we present an analysis of novel drug/target predictions, focusing on those that were not obvious based on known pharmacological crosstalk. Considering those cases where the predicted target was an enzyme with known 3D structure allowed incorporation of information from molecular docking and protein binding pocket similarity in addition to ligand-based comparisons. Taken together, the combination of orthogonal information sources led to investigation of a surprising predicted relationship between a transcription factor and an enzyme, specifically, PPARα and the cyclooxygenase enzymes. These predictions were confirmed by direct biochemical experiments which validate the approach and show for the first time that PPARα agonists are cyclooxygenase inhibitors.

We introduce the ForceGen method for 3D structure generation and conformer elaboration of drug-like small molecules. ForceGen is novel, avoiding use of distance geometry, molecular templates, or simulation-oriented stochastic sampling. The method is primarily driven by the molecular force field, implemented using an extension of MMFF94s and a partial charge estimator based on electronegativity-equalization. The force field is coupled to algorithms for direct sampling of realistic physical movements made by small molecules. Results are presented on a standard benchmark from the Cambridge Crystallographic Database of 480 drug-like small molecules, including full structure generation from SMILES strings. Reproduction of protein-bound crystallographic ligand poses is demonstrated on four carefully curated data sets: the ConfGen Set (667 ligands), the PINC cross-docking benchmark (1062 ligands), a large set of macrocyclic ligands (182 total with typical ring sizes of 12-23 atoms), and a commonly used benchmark for evaluating macrocycle conformer generation (30 ligands total). Results compare favorably to alternative methods, and performance on macrocyclic compounds approaches that observed on non-macrocycles while yielding a roughly 100-fold speed improvement over alternative MD-based methods with comparable performance.

This study is aimed at utilizing Neem Leaves powder as low cost adsorbent material for removal of Cr-(VI) from aqueous solution. Adsorption is an important process used for removal of colour, odour, turbidity, metal ions and reduction of COD. In adsorption, the solute present in dilute concentration in liquid or gas phase is extracted by contacting with suitable solid adsorbent so that the transfer of the component first takes place on the surface of solid and then into the pore of the solid. Neem Leaves powder Adsorbent used in present study is prepared at Laboratory scale which is very effective to remove chromium from its aqueous solution. This study describes the detailed experimental procedure to obtain Adsorption Equilibrium and the Effect of various parameters such pH, agitation time, initial metal ion concentration & adsorbent doses on batch technique.

SUMMARYA field experiment was carried out at the farm of Indian Agricultural Research Institute, New Delhi to quantify the effect of elevated carbon dioxide (CO2) and different levels of N fertiliser application on nitrous oxide (N2O) and carbon dioxide (CO2) emissions from soil under maize. The experiment included five treatments: 60 kg N ha−1under ambient CO2(385 ppm) in open plots, 120 kg N ha−1under ambient CO2(385 ppm) in open plots, 160 kg N ha−1under ambient CO2(385 ppm) in open plots, 120 kg N ha−1under ambient CO2(385 ppm) in open top chambers (OTC) and 120 kg N ha−1under elevated CO2(500 ± 50 ppm) in the OTC. Peaks of N2O flux were observed after every dose of N application. Cumulative N2O emission was 13% lower under ambient CO2as compared to the elevated CO2concentrations. There was an increase in CO2emissions with application of N from 60 kg ha−1to 160 kg ha−1. Higher yield and root biomass was observed under higher N treatment (160 kg N ha−1). There was no significant increase in maize yield under elevated CO2as compared to ambient CO2. The carbon emitted was more than the carbon fixed under elevated CO2as compared to ambient CO2levels. The carbon efficiency ratio (C fixed/C emitted) was highest in ambient CO2treatment in the OTC.

Multi-stimuli responsive porous silica nanoparticles for controlled release of insulin were synthesized by tethering insulin molecules onto boronic acid-functionalized mesoporous silica nanoparticles (BA-MSNs) and then coating the BA-MSNs with the bioadhesive and pH-sensitive polymer polyacrylic acid (PAA). The insulin molecules were conjugated onto the exterior surfaces of BA-MSNs via gluconic acid linker groups [or by making first the gluconic acid-modified insulin (Gins)]. The surfaces of the resulting BA-MSNs containing Gins were coated with PAA, which was used to protect the entrapped insulin from undergoing possible enzymatic degradations in such locations as the gastrointestinal (GI) tract. The PAA, which has excellent dispersibility and adherence to the mucosa, might also allow the permeation of such nanoparticles through the colon, and thereby improve their potential application for insulin delivery. The drug release properties of the resulting nanoparticles, denoted PAA-Gins-BA-MSNs, as well as their control samples were studied in enzyme-free simulated gastric fluid (SGF) (pH = 2.0), simulated intestinal fluid (SIF) (pH = 6.8), and phosphate buffer saline (PBS) (pH = 7.4). Because of their shrinkage at low pH and swelling at high pH, the PAA-coated MSNs exhibited pH-dependent insulin release properties. Besides pH, glucose was shown to trigger the release of insulin from the nanoparticles, which demonstrates the nanoparticles' multi-stimuli-responsive properties for controlled release of insulin. Finally, we show that the PAA-coated MSNs were non-cytotoxic.

A recently developed frequency-modulated thermal wave imaging (FMTWI) has been applied for subsurface defect detection of jute fibre-reinforced polypropylene (PP) matrix composite. Composites are subject to manufacturing and in-service defects like voids, delamination, cracks and so on. Active thermography like lock-in thermography (LT) and pulsed thermography (PT) has been widely used for non-destructive testing of composites and laminates. FMTWI may be viewed as a superposed LT, wherein multiple frequency response is obtained through single measurement. It is very much suitable for newly developed material for which the thermal properties are not well established, thereby impeding the choice of appropriate frequency for conventional LT. In this article, FMTWI is applied to detect and characterize artificially generated subsurface defects in jute–PP composite. The measurements also show the effect of frequency on the depth of defect detection and accuracy.

The pharmacokinetic and safety profiles of clinical drug candidates are greatly influenced by their requisite physicochemical properties. In particular, it has been shown that 2D molecular descriptors such as fraction of Sp3 carbon atoms (Fsp3) and number of stereo centers correlate with clinical success. Using the proteomic off-target hit rate of nicotinic ligands, we found that shape-based 3D descriptors such as the radius of gyration and shadow indices discriminate off-target promiscuity better than do Fsp3 and the number of stereo centers. We have deduced the relevant descriptor values required for a ligand to be nonpromiscuous. Investigating the MDL Drug Data Report (MDDR) database as compounds move from the preclinical stage toward the market, we have found that these shape-based 3D descriptors predict clinical success of compounds at preclinical and phase1 stages vs compounds withdrawn from the market better than do Fsp3 and LogD. Further, these computed 3D molecular descriptors correlate well with experimentally observed solubility, which is among well-known physicochemical properties that drive clinical success. We also found that about 84% of launched drugs satisfy either Shadow index or Fsp3 criteria, whereas withdrawn and discontinued compounds fail to meet the same criteria. Our studies suggest that spherical compounds (rather than their elongated counterparts) with a minimal number of aromatic rings may exhibit a high propensity to advance from clinical trials to market.

The geological storage of anthropogenic carbon dioxide (CO2) is one method of reducing the amount of CO2 released into the atmosphere. Monitoring programs typically determine baseline conditions in surface and near-surface environments before, during, and after CO2 injection to evaluate if impacts related to injection have occurred. Because CO2 concentrations in groundwater fluctuate naturally due to complex geochemical and geomicrobiologicalinteractions, a clear understanding of the baseline behavior of CO2 in groundwater near injection sites is important. Numerous ways of measuring aqueous CO2 in the field and lab are currently used, but most methods have significant shortcomings (e.g., are tedious, lengthy, have interferences, or have significant lag time before a result is determined). In this study, we examined the effectiveness of two novel CO2 detection methods and their ability to rapidly detect CO2in shallow groundwater monitoring wells associated with the Illinois Basin –Decatur Project geological sequestration site. The CarboQC beverage carbonation meter was used to measure the concentration of CO2 in water by monitoring temperature and pressure changes and calculating the PCO2 from the ideal gas law. Additionally, a non-dispersive infrared (NDIR) CO 2sensor enclosed in a gas-permeable, water-impermeable membrane measured CO2by determining an equilibrium concentration. Results showed that the CarboQCmore » method provided rapid (< 3 min) and repeatable results under field conditions within a measured concentration range of 15 –125 mg/L CO2. The NDIR sensor results correlated well (r2= 0.93) with the CarboQC data, but CO2 equilibration required at least 15 minutes, making the method somewhat less desirable under field conditions. In contrast, NDIR-based sensors have a greater potential for long-term deployment. Both systems are adaptable to in-line groundwater sampling methods. Other specific advantages and disadvantages associated with the two approaches, and anomalies associated with specific samples, are discussed in greater detail in this poster.« less

With the development of nuclear power programme, an additional consideration outside the existing radiation protection framework appeared: the need to assess not only the level of exposure, but also to take into consideration the accidents which could release large inventories of radioactivity. With the expansion of nuclear commitments, the inventories of Tritium are bound to increase. The possible use of tritium as the fuel for fusion reactors in the near future may result in an additional source of tritium. Swiss albino mice of 1, 2, 3, 4 & 6 weeks of age were injected with tritiated water (HTO) at the dose 111 kBq/gram body weight and the animals from each age group autopsied on 1, 7 and 30 days post- injection. The mouse show radiovulnerability with a capability to repair and recover from the rendered damage during the first half (1 week to 3 week) of postnatal development, whereas during the second half (4 week to 6 week of age) a tendency towards radioresistance is achieved. The presentation is an attempt to revisit the behaviour of tritium with its possible implications on the environment in accordance with the presently projected radiation protection framework.

Computational methods for predicting ligand affinity where no protein structure is known generally take the form of regression analysis based on molecular features that have only a tangential relationship to a protein/ligand binding event. Such methods have utility in retrospective rationalization of activity patterns of substituents on a common scaffold, but are limited when either multiple scaffolds are present or when ligand alignment varies significantly based on structural changes. In addition, such methods generally assume independence and additivity of effect from scaffold substituents. Collectively, these non-physical modeling assumptions sharply limit the utility of widely used QSAR approaches for prospective prediction of ligand activity. The recently introduced Surflex-QMOD approach, by virtue of constructing physical models of binding sites, comes closer to a modeling approach that is congruent with protein ligand binding events. A set of congeneric CDK2 inhibitors showed that induced binding pockets can be quite congruent with the enzyme's active site but that model predictivity within a chemical series does not necessarily depend on congruence. Muscarinic antagonists were used to show that the QMOD approach is capable of making accurate predictions in cases where highly non-additive structure activity effects exist. The QMOD method offers a means to go beyond non-causative correlations in QSAR analysis.

No-till farming in wheat is being practiced in the rice–wheat system of the Indo-Gangetic plains of south Asia for resource conservation. No-tillage leads to mitigation of carbon dioxide emission, but may emit more nitrous oxide (N 2 O) as compared to conventional tillage reducing mitigation benefit. The aim of this study was assessment of N 2 O emission in wheat grown under conventional and no-tillage and its mitigation using two new nitrification inhibitors, viz. S-benzylisothiouronium butanoate (SBT-butanoate) and S-benzylisothiouronium furoate (SBT-furoate). Cumulative emission of N 2 O-N was higher under no-tillage by 12.2% with urea fertilization and from 4.1 to 4.8% for the inhibitor treatments as compared to the conventional tillage. In no-tillage total emission of N 2 O-N reduced from 0.43% of applied N with urea to 0.29% of applied N with SBT-furoate treatment. The N 2 O-N emissions in SBT-butanoate treatment were at par with the standard dicyandiamide (DCD) inhibitor treatment. Water-filled pore space (WFPS) was higher on most days under no-tillage, with the largest emissions (>1000 μg N 2 O-N m −2 day −1 ) coming with nitrification of ammonium-N present in soil below 60% WFPS. Carbon efficiency ratio was highest (48.1) from SBT-furoate treatment under conventional tillage. The nitrification inhibitors used in the study increased yield of wheat, reduced global warming potential by 8.9–19.5% over urea treatment and may be used to mitigate N 2 O emission.

In this paper, we present a systematic study of the role of metal/semiconductor nanowire (NW) contact in back-gated Ge and Si NW Schottky-barrier (SB) FETs. Our results show that the performance of such devices is largely dominated by the carrier injection efficiency at the source contact, which, in turn, is controlled by metal contact depth and gate bias. Using low-temperature annealing of back-gated Ge and Si NW SB FETs with nickel (Ni) contacts as source and drain, we monitor the evolution of the device current as the contact metal progressively diffuses into the NWs. The drain current, which is measured at a given gate and drain bias, first increases as the contact metal diffuses into the NW, reaches a maximum, and subsequently decreases. These results can be explained by the interplay between carrier injection efficiency through the metal/NW SB, which increases with the metal contact depth, and the number of available states in the NW between contact and the bottom oxide, which decreases with the metal contact depth.

Computational methods for predicting ligand affinity where no protein structure is known generally take the form of regression analysis based on molecular features that have only a tangential relationship to a protein/ligand binding event. Such methods have limited utility when structural variation moves beyond congeneric series. We present a novel approach, based on the multiple-instance learning method of Compass, where a physical model of a binding site is induced from ligands and their corresponding activity data. The model consists of molecular fragments that can account for multiple positions of literal protein residues. We demonstrate the method on 5HT1a ligands by training on a series with limited scaffold variation and testing on numerous ligands with variant scaffolds. Predictive error was between 0.5 and 1.0 log units (0.7–1.4 kcal/mol), with statistically significant rank correlations. Accurate activity predictions of novel ligands were demonstrated using a validation approach where a small number of ligands of limited structural variation known at a fixed time point were used to make predictions on a blind test set of widely varying molecules, some discovered at a much later time-point.

This article reports the synthesis and characterization of four Ni(II) Schiff base complexes, [Ni(L)(H2O)], where H2L = N-(dehydroacetic acid)-thiosemicarbazide (H2dha-tsc), N-(dehydroacetic acid)-4-methyl-3-thiosemicarbazide (H2dha-mtsc), N-(dehydroacetic acid)-4-phenyl-3-thiosemicarbazide (H2dha-ptsc), or N-(dehydroacetic acid)-4-phenylsemicarbazide (H2dha-psc). The nature of bonding and stereochemistry of these complexes have been deduced from elemental analysis, infrared and electronic spectral studies, molar conductance, magnetic measurements, mass spectrometry, thermogravimetric analysis, 1H NMR and 13C NMR studies, and cyclic voltammetry. The stabilities of the complexes were determined in both solid state and solution. Molecular geometry optimizations and vibrational frequency calculations were performed with Gaussian 09 software package using density functional theory (DFT) with B3LYP/6-311G for a ligand (dha-ptscH2) and B3LYP/LANL2DZ combination for [Ni(dha-mtsc)(H2O)]. Based on the combined experimental and theoretical studies, square planar geometry has been proposed for the Ni(II) complexes. The Schiff base ligands and their metal complexes were screened for antibacterial activities against gram-negative bacteria (Escherichia coli ) at different concentrations to get their minimum inhibition concentration values. The bactericidal activity was enhanced in metal complexes as compared to free ligands.

Surflex-Dock employs an empirically derived scoring function to rank putative protein-ligand interactions by flexible docking of small molecules to proteins of known structure. The scoring function employed by Surflex was developed purely on the basis of positive data, comprising noncovalent protein-ligand complexes with known binding affinities. Consequently, scoring function terms for improper interactions received little weight in parameter estimation, and an ad hoc scheme for avoiding protein-ligand interpenetration was adopted. We present a generalized method for incorporating synthetically generated negative training data, which allows for rigorous estimation of all scoring function parameters. Geometric docking accuracy remained excellent under the new parametrization. In addition, a test of screening utility covering a diverse set of 29 proteins and corresponding ligand sets showed improved performance. Maximal enrichment of true ligands over nonligands exceeded 20-fold in over 80% of cases, with enrichment of greater than 100-fold in over 50% of cases.

Array-based comparative genomic hybridization (CGH) allows for the simultaneous examination of thousands of genomic loci at 1-2 Mb resolution. Copy number alterations detected by array-based CGH can aid in the identification and localization of cancer causing genes. Here we report the results of array-based CGH in a set of 125 primary colorectal tumors hybridized onto an array consisting of 2463 bacterial artificial chromosome clones. On average, 17.3% of the entire genome was altered in our samples (8.5 +/- 6.7% gained and 8.8 +/- 7.3% lost). Losses involving 8p, 17p, 18p or 18q occurred in 37, 46, 49 and 60% of cases, respectively. Gains involving 8q or 20q were observed 42 and 65% of the time, respectively. A transition from loss to gain occurred on chromosome 8 between 41 and 48 Mb, with 25% of cases demonstrating a gain of 8p11 (45-53 Mb). Chromosome 8 also contained four distinct loci demonstrating high-level amplifications, centering at 44.9, 60, 92.7 and 144.7 Mb. On 20q multiple high-level amplifications were observed, centering at 32.3, 37.8, 45.4, 54.7, 59.4 and 65 Mb. Few differences in DNA copy number alterations were associated with tumor stage, location, age and sex of the patient. Microsatellite stable and unstable (MSI-H) tumors differed significantly with respect to the frequency of alterations (20 versus 5%, respectively, P < 0.01). Interestingly, MSI-H tumors were also observed to have DNA copy number alterations, most commonly involving 8q. This high-resolution analysis of DNA copy number alterations in colorectal cancer by array-based CGH allowed for the identification of many small, previously uncharacterized, genomic regions, such as on chromosomes 8 and 20. Array-based CGH was also able to identify DNA copy number changes in MSI-H tumors.

The majority of drug targets for small molecule therapeutics are proteins whose three-dimensional structure is not known to sufficient resolution to permit structure-based design. All three-dimensional QSAR approaches have a requirement for some hypothesis of ligand conformation and alignment, and predictions of molecular activity critically depend on this ligand-based binding site hypothesis. The molecular similarity function used in the Surflex docking system, coupled with quantitative pressure to minimize overall molecular volume, forms an effective objective function for generating hypotheses of bioactive conformations of sets of small molecules binding to their cognate proteins. Results are presented, assessing utility of the method for ligands of the serotonin, histamine, muscarinic, and GABA(A) receptors. The Surflex similarity module (Surflex-Sim) was able, in each case, to distinguish true ligands from random compounds using models constructed from just two or three known ligands. True positive rates of 60% were achieved with false positive rates of 0-3%; the theoretical enrichment rates were over 150-fold compared with random screening. The methods are practically applicable for rational design of ligands and for high-throughput virtual screening and offer competitive performance to many structure-based docking algorithms.

The present investigation was aimed at determining the spectrum of activity of the methanolic extract of Clitoria ternatea (CT) on the CNS. The CT was studied for its effect on cognitive behavior, anxiety, depression, stress and convulsions induced by pentylenetetrazol (PTZ) and maximum electroshock (MES). To explain these effects, the effect of CT was also studied on behavior mediated by dopamine (DA), noradrenaline, serotonin and acetylcholine. The extract decreased time required to occupy the central platform (transfer latency, TL) in the elevated plus maze (EPM) and increased discrimination index in the object recognition test, indicating nootropic activity. The extract was more active in the object recognition test than in the EPM. The extract increased occupancy in the open arm of EPM by 160% and in the lit box of the light/dark exploration test by 157%, indicating its anxiolytic activity. It decreased the duration of immobility in tail suspension test (suggesting its antidepressant activity), reduced stress-induced ulcers and reduced the convulsing action of PTZ and MES. The extract exhibited tendency to reduce the intensity of behavior mediated via serotonin and acetylcholine. The effect on DA- and noradrenaline-mediated behavior was not significant. In conclusion, the extract was found to possess nootropic, anxiolytic, antidepressant, anticonvulsant and antistress activity. Further studies are necessary to isolate the active principle responsible for the activities and to understand its mode of action.

Surflex is a fully automatic flexible molecular docking algorithm that combines the scoring function from the Hammerhead docking system with a search engine that relies on a surface-based molecular similarity method as a means to rapidly generate suitable putative poses for molecular fragments. Results are presented evaluating reliability and accuracy of dockings compared with crystallographic experimental results on 81 protein/ligand pairs of substantial structural diversity. In over 80% of the complexes, Surflex's highest scoring docked pose was within 2.5 A root-mean-square deviation (rmsd), with over 90% of the complexes having one of the top ranked poses within 2.5 A rmsd. Results are also presented assessing Surflex's utility as a screening tool on two protein targets (thymidine kinase and estrogen receptor) using data sets on which competing methods were run. Performance of Surflex was significantly better, with true positive rates of greater than 80% at false positive rates of less than 1%. Docking time was roughly linear in number of rotatable bonds, beginning with a few seconds for rigid molecules and adding approximately 10 s per rotatable bond.

Effects of various factors, such as light intensity, polarizability of n-alcohol solvents, addition of colorants, and viscosity of solutions on the kinetics of the photoisomerization of therapeutically effective E-isomer of sorivudine to its less effective Z-isomer were studied. Solutions of known concentrations of E-isomer or Z-isomer in water or in a series of n-alcohols were directly exposed to ultraviolet (UV) A light, or visible light of 400 or 900 foot candles (fc). E-isomer solutions containing various colorants at 1% w/v, or in a series of poloxamer solutions of different viscosities, were also exposed to 400 or 900 fc light. Using the stability-indicating HPLC assay, which showed mass-balance between the starting isomer and the converting isomer, the kinetics of photoisomerization were monitored. The photoisomerization reaction, which takes place on the vinyl side chain, was found to be a first-order reversible reaction. In water, the rate of conversion of E-isomer to Z-isomer was faster than that of Z-isomer to E-isomer, since, E-isomer with higher extinction coefficient absorbed substantially more light than Z-isomer. The rate of photoisomerization increased with the intensity of the visible light and was very rapid in the presence of UV A light (300 to 400 nm), which is to be expected based on the 239 nm and 283 nm absorption maxima of sorivudine. Addition of water-soluble colorants retarded the photoisomerization process significantly, especially as the maximum absorption wavelengths (lambda max) of the colorants approached the UV region. The rate of photoisomerization increased with increasing polarizability (alpha s) of the n-alcohol solvents. Polarizable solvents such as alcohols could compensate for the electron density built up in the excited state, and thus facilitated the photoisomerization process. The rate of photoisomerization decreased as the viscosity of solution increased. This may be attributed to the fact that the twisting of the C=C bond in the excited state can be inhibited by the friction imposed by the viscous medium.