Integrating water quality data with a Bayesian network model to improve spatial and temporal phosphorus attribution: Application to the Maumee River Basin.

Surface water nutrient pollution, the primary cause of eutrophication, remains a major environmental concern in Western Lake Erie despite intergovernmental efforts to regulate nutrient sources. The Maumee River Basin has been the largest nutrient contributor. The two primary nutrient sources are inorganic fertilizer and livestock manure applied to croplands, which are later carried to the streams via runoff and soil erosion. Prior studies of nutrient source attribution have focused on large watersheds or counties at annual time scales. Source attribution at finer spatiotemporal scales, which enables more effective nutrient management, remains a substantial challenge. This study aims to address this challenge by developing a generalizable Bayesian network model for phosphorus source attribution at the subwatershed scale (12-digit Hydrologic Unit Code). Since phosphorus release is uncertain, we combine excess phosphorus derived from manure and fertilizer application and crop uptake data, flow information simulated by the SWAT model, and in-stream water quality measurements using Approximate Bayesian Computation to derive a posterior that attributes phosphorus contributions to subwatersheds. Our results show significant variability in subwatershed-scale phosphorus release that is lost in coarse-scale attribution. Phosphorus contributions attributed to the subwatersheds are on average lower than the excess phosphorus estimated by the nutrient balance approach currently adopted by environmental agencies. Fertilizer contributes more soluble reactive phosphorus than manure, while manure contributes most of the unreactive phosphorus. While developed for the specific context of Maumee River Basin, our lightweight and generalizable model framework could be adapted to other regions and pollutants and could help inform targeted environmental regulation and enforcement.

Bivalent EGFR-Targeting DARPin-MMAE Conjugates.

Epidermal growth factor receptor (EGFR) is a validated tumor marker overexpressed in various cancers such as squamous cell carcinoma (SSC) of the head and neck and gliomas. We constructed protein-drug conjugates based on the anti-EGFR Designed Ankyrin Repeat Protein (DARPin) E01, and compared the bivalent DARPin dimer (DD1) and a DARPin-Fc (DFc) to the monomeric DARPin (DM) and the antibody derived scFv425-Fc (scFvFc) in cell culture and a mouse model. The modular conjugation system, which was successfully applied for the preparation of protein-drug and -dye conjugates, uses bio-orthogonal protein-aldehyde generation by the formylglycine-generating enzyme (FGE). The generated carbonyl moiety is addressed by a bifunctional linker with a pyrazolone for a tandem Knoevenagel reaction and an azide for strain-promoted azide-alkyne cycloaddition (SPAAC). The latter reaction with a PEGylated linker containing a dibenzocyclooctyne (DBCO) for SPAAC and monomethyl auristatin E (MMAE) as the toxin provided the stable conjugates DD1-MMAE (drug-antibody ratio, DAR = 2.0) and DFc-MMAE (DAR = 4.0) with sub-nanomolar cytotoxicity against the human squamous carcinoma derived A431 cells. In vivo imaging of Alexa Fluor 647-dye conjugates in A431-xenografted mice bearing subcutaneous tumors as the SCC model revealed unspecific binding of bivalent DARPins to the ubiquitously expressed EGFR. Tumor-targeting was verified 6 h post-injection solely for DD1 and scFvFc. The total of four administrations of 6.5 mg/kg DD1-MMAE or DFc-MMAE twice weekly did not cause any sequela in mice. MMAE conjugates showed no significant anti-tumor efficacy in vivo, but a trend towards increased necrotic areas (p = 0.2213) was observed for the DD1-MMAE (n = 5).

Site-Specific Conjugation Strategy for Dual Antibody-Drug Conjugates Using Aerobic Formylglycine-Generating Enzymes.

Multiple, site-specific protein conjugation is increasingly attractive for the generation of antibody-drug conjugates (ADCs). As it is important to control the number and position of cargoes in an ADC, position-selective generation of reactive sites in the protein of interest is required. Formylglycine (FGly) residues are generated by enzymatic conversion of cysteine residues embedded in a certain amino acid sequence motif with a formylglycine-generating enzyme (FGE). The addition of copper ions increases FGE activity leading to the conversion of cysteines within less readily accepted sequences. With this tuned enzyme activity, it is possible to address two different recognition sequences using two aerobic formylglycine-generating enzymes. We demonstrate an improved and facile strategy for the functionalization of a DARPin (designed ankyrin repeat protein) and the single-chain antibody scFv425-Fc, both directed against the epidermal growth factor receptor (EGFR). The single-chain antibody was conjugated with monomethyl auristatin E (MMAE) and carboxyfluorescein (CF) and successfully tested for receptor binding, internalization, and cytotoxicity in cell culture, respectively.

Budyko-Based Long-Term Water and Energy Balance Closure in Global Watersheds From Earth Observations.

Earth observations offer potential pathways for accurately closing the water and energy balance of watersheds, a fundamental challenge in hydrology. However, previous attempts based on purely satellite-based estimates have focused on closing the water and energy balances separately. They are hindered by the lack of estimates of key components, such as runoff. Here, we posit a novel approach based on Budyko's water and energy balance constraints. The approach is applied to quantify the degree of long-term closure at the watershed scale, as well as its associated uncertainties, using an ensemble of global satellite data sets. We find large spatial variability across aridity, elevation, and other environmental gradients. Specifically, we find a positive correlation between elevation and closure uncertainty, as derived from the Budyko approach. In mountainous watersheds the uncertainty in closure is 3.9 ± 0.7 (dimensionless). Our results show that uncertainties in terrestrial evaporation contribute twice as much as precipitation uncertainties to errors in the closure of water and energy balance. Moreover, our results highlight the need for improving satellite-based precipitation and evaporation data in humid temperate forests, where the closure error in the Budyko space is as high as 1.1 ± 0.3, compared to only 0.2 ± 0.03 in tropical forests. Comparing the results with land surface model-based data sets driven by in situ precipitation, we find that Earth observation-based data sets perform better in regions where precipitation gauges are sparse. These findings have implications for improving the understanding of global hydrology and regional water management and can guide the development of satellite remote sensing-based data sets and Earth system models.

Small-Molecule Inhibitor Prevents Insulin Fibrillogenesis and Preserves Activity.

Amyloidosis is a well-known but poorly understood phenomenon caused by the aggregation of proteins, often leading to pathological conditions. For example, the aggregation of insulin poses significant challenges during the preparation of pharmaceutical insulin formulations commonly used to treat diabetic patients. Therefore, it is essential to develop inhibitors of insulin aggregation for potential biomedical applications and for important mechanistic insights into amyloidogenic pathways. Here, we have identified a small molecule M1, which causes a dose-dependent reduction in insulin fibril formation. Biophysical analyses and docking results suggest that M1 likely binds to partially unfolded insulin intermediates. Further, M1-treated insulin had lower cytotoxicity and remained functionally active in regulating cell proliferation in cultured Drosophila wing epithelium. Thus, M1 is of great interest as a novel agent for inhibiting insulin aggregation during biopharmaceutical manufacturing.

Two-fold Bioorthogonal Derivatization by Different Formylglycine-Generating Enzymes.

Formylglycine-generating enzymes are of increasing interest in the field of bioconjugation chemistry. They catalyze the site-specific oxidation of a cysteine residue to the aldehyde-containing amino acid Cα -formylglycine (FGly). This non-canonical residue can be generated within any desired target protein and can subsequently be used for bioorthogonal conjugation reactions. The prototypic formylglycine-generating enzyme (FGE) and the iron-sulfur protein AtsB display slight variations in their recognition sequences. We designed specific tags in peptides and proteins that were selectively converted by the different enzymes. Combination of the different tag motifs within a single peptide or recombinant protein enabled the independent and consecutive introduction of two formylglycine residues and the generation of heterobifunctionalized protein conjugates.

Synthesis of 3,5-dihydroxy-7,8-dimethoxy-2-(4-methoxyphenyl)benzopyran-4-one derivatives as anticancer agents.

Different alkyl amide (15a-l) and alkyl amine (16a-e) derivatives of 7,8-dimethoxy-3-hydroxy-2-(4-methoxyphenyl)benzopyran-4-one were synthesized and evaluated for their anticancer activity against five different cancer cell lines using SRB assay. Compounds 15e, 15i, 15j and 16a-e showed significant anticancer activity within the range of IC50 2.58-34.86µM. The most promising molecule, 16c, was further analyzed for its effect on cell cycle and apoptosis of estrogen receptor positive cancer cells (MCF-7 cells) which showed that 16c triggered apoptosis in MCF-7 cells and arrested cells population at sub-G0 (apoptotic) and G2M phase. In tubulin polymerization assay, 16c interfered with kinetics of tubulin polymerization.

Natural antitubulin agents: importance of 3,4,5-trimethoxyphenyl fragment.

Microtubules are polar cytoskeletal filaments assembled from head-to-tail and comprised of lateral associations of α/ß-tubulin heterodimers that play key role in various cellular processes. Because of their vital role in mitosis and various other cellular processes, microtubules have been attractive targets for several disease conditions and especially for cancer. Antitubulin is the most successful class of antimitotic agents in cancer chemotherapeutics. The target recognition of antimitotic agents as a ligand is not much explored so far. However, 3,4,5-trimethoxyphenyl fragment has been much highlighted and discussed in such type of interactions. In this review, some of the most important naturally occurring antimitotic agents and their interactions with microtubules are discussed with a special emphasis on the role of 3,4,5-trimethoxyphenyl unit. At last, some emerging naturally occurring antimitotic agents have also been tabulated.

Immediate effect of Kinesio taping on shoulder muscle strength and range of motion in healthy individuals: A randomised trial.

BACKGROUND: Taping is widely used in the field of rehabilitation as both a means of treatment and prevention of sports-related injuries. In recent years, the use of Kinesio tape has become increasingly popular; it can be applied to virtually any muscle or joint in the body. Kinesio tape and its strength-enhancing properties have been the focus of recent research based on the neuromuscular facilitator theory. There has been, however, inconclusive evidence to either support or refute this theory. OBJECTIVE: This study investigated the immediate effect of Kinesio taping (KT) on peak torque of shoulder external rotators muscle and shoulder external and internal range of motion (ROM) in healthy individuals. METHODS: This was a single-blinded, placebo-controlled, randomised trial. A total of 39 participants were randomly allocated into three groups. Two main variables were measured-peak torque of shoulder external rotation at two isokinetic speeds (60°/s and 180°/s) was measured with a Biodex isokinetic dynamometer, and shoulder rotation ROM was measured with a standard goniometer. Dependent variables were measured after the application of three different taping conditions-no taping (NT), KT, and placebo taping (PT)-on each participant with 3-day intervals. RESULTS: The mean peak torque at speeds of 60°/s and 180°/s demonstrated no significant difference among the three taping conditions. No significant difference in external rotation range of motion was detected among the three taping conditions. The PT condition led to a significantly smaller mean internal range of motion value than KT and PT (p <0.016). CONCLUSION: Overall, KT did not cause significant difference in shoulder external rotation peak torque, and shoulder internal and external range of motion in healthy individuals.

Fabrication and characterization of binary composite MgO/CuO nanostructures for the efficient photocatalytic ability to eliminate organic contaminants: A detailed spectroscopic analysis.

Design and eco-friendly fabrication of affordable and sustainable materials for the treatment of wastewater consisting of dyes, antibiotics, and other harmful substances has always been demanding. Untreated wastewater being released from industries imposes serious threats to our ecosystem, seeking convenient approaches to diminish this alarming issue. Here in this work, we synthesized MgO/CuO nanocomposites from a plant extract of Ammi visnaga L. and then employed these nanocomposites for the treatment of organic dye (methylene blue). We characterized the synthesized nanocomposites by dynamic light scattering (DLS), zeta potential, scanning electron microscopy (SEM), atomic force microscopy (AFM), transmission electron microscopy (TEM), x-ray diffraction (XRD), and X-ray photoelectron microscopy (XPS). DLS presented information about the explicit size of nanocomposites, while the surface charge was examined by zeta potential. XRD provided detailed information about the crystalline behavior and the information regarding surface morphology and size was extracted by SEM, TEM, and AFM. Moreover, the fabricated nanocomposites were used as a photocatalyst in the treatment of methylene blue. The overall catalytic reaction took an hour to complete, and the value of percentage degradation was 98 %. Substantially, a detailed account of the kinetics, rate of reaction, and mechanism is also fostered in the context. The presented study can assist scientists and researchers around the world to reproduce the results and use them to apply them on a broader scale.

Preparation and Spectrochemical characterization of Ni-doped ZnS nanocomposite for effective removal of emerging contaminants and hydrogen Production: Reaction Kinetics, mechanistic insights.

In this study, we report the successful synthesis of Ni-doped ZnS nanocomposite via a green route using ethanolic crude extract of Avena fatua. The as-synthesized nanocomposite was comprehensively characterized using Dynamic light scattering (DLS), Zeta potential, scanning electron microscopy (SEM), Transmission electron microscopy (TEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FTIR), and Atomic force microscopy (AFM). These analyses provided detailed insights into the size, morphology, composition, surface properties, and structural characteristics of the nanocomposite. Subsequently, the synthesized nanocomposite was evaluated for their photocatalytic performance against the organic dye Methyl orange. Remarkably, the nanocomposite exhibited rapid and efficient degradation of Methyl orange, achieving 90 % degradation within only 30 min of irradiation under UV light. Moreover, the photocatalyst demonstrated an exceptional hydrogen production rate, reaching 167.73 µmolg-1h-1, which is approximately 4.5 times higher than that of its pristine counterparts. These findings highlight the significant potential of Ni-doped ZnS nanocomposite as highly efficient photocatalysts for wastewater treatment and hydrogen production applications.

Pharmacophore-based virtual screening, molecular docking, and molecular dynamics studies for the discovery of novel FLT3 inhibitors.

FLT3 is considered a potential target of acute myeloid leukemia therapy. In this study, we applied a computer-aided methodology unifying molecular docking and pharmacophore screening to identify potent inhibitors against FLT3. To investigate the pharmacophore area and binding mechanism of FLT3, the reported co-crystallized Gilteritinib ligand was docked into the active site using Glide XP. Based on the docking results, we identified structure-based pharmacophore characteristics resistant to potent FLT3 inhibitors. The best hypothesis was corroborated using test and decoy sets, and the verified hypo was utilized to screen the chemical database. The hits from the pharmacophore-based screening were then screened again using a structure-based method that included molecular docking at various precisions; the selected molecules were further examined and refined using drug-like filters and ADMET analysis. Finally, two hits were picked out for molecular dynamic simulation. The results showed two hits were expected to have potent inhibitory activity and excellent ADMET characteristics, and they might be used as new leads in the development of FLT3 inhibitors.Communicated by Ramaswamy H. Sarma.

Masoprocol: a promising candidate for targeting insulin resistance by inhibiting resistin with optimal druglikeness Potentials: an in silico approach.

Resistin is a cysteine-rich secretory hormone that induces resistance to insulin, and its elevated expression is correlated with the onset of diabetes and several related metabolic disorders. Resistin performs its inhibitory role by connecting three identical subunits through Cys22-based disulfide linkages. The necessity to inhibit the formation of resistin trimer is one of the essential means to prevent the aggravation of diabetes mellitus type 2, obesity, and atherosclerosis. This study was conducted to screen the clinically approved drugs to find the most potent one to inhibit resistin with the best pharmacokinetics and drug-likeness properties. A total of 4654 clinically approved drugs were docked against the Cys22 residue of resistin. The top ten drugs with the highest high-precision (XP) docking scores were selected. Ioversol and masoprocol showed the highest XP docking and Molecular Mechanics-Generalized Born Surface Area (MMGBSA) scores, respectively, with double hydrogen bonding with the targeted Cys22. Molecular dynamics (MD) simulations showed that the masoprocol-resistin complex exhibited lower root mean square deviation (RMSD), radius of gyration, and root mean square fluctuation (RMSF) values than those observed in the ioversol-resistin complex. Both drugs induced drastic conformational changes in resistin monomer interactions. However, ioversol did not prove satisfying drug-likeness properties, while masoprocol showed the most favourable pharmacokinetic and drug-likeness properties. This study has demonstrated that masoprocol offers a novel inhibitory effect on resistin with the highest ligand affinity, making it a promising drug for combating insulin resistance.Communicated by Ramaswamy H. Sarma.

Hemagglutinin 3 and 8 can be the most efficient influenza subtypes for human host invasion; a comparative in silico approach.

The severity of the influenza virus infection is largely determined by its ability to invade the human host receptor. This critical step is conducted by utilizing hemagglutinin (HA) due to its binding with sialic acid 2,6 (SA). Though 18 subtypes (H1-H18) of HA have been identified, the most efficient one for conducting the host entry has not yet been resolved. This study aims to assess the severity of infections for HA variants by conducting a comparative docking of H1-H18 with the human SA receptor. Eighteen viral 3D structures were retrieved, minimized, and optimized for docking with human SA. In all retrieved structures, five conserved amino acid residues were selected for docking with human SA. Special protein grids were prepared by locating these five residues in the 18 selected subtypes. Results showed that H3 and H8 exerted the highest standard precision and extra precision docking scores, and the highest binding affinities with the human SA, respectively. Phylogenetic analyses confirmed the actual positioning of the selected 3D structures and showed these docked structures belonged to their usual classes due to the extremely close distances found in each docked subtype compared with its corresponding non-docked structures. H8-SA showed slightly better RMSD and SASA values than H3-SA, while H3-SIA showed more favourable radius of gyration scores than H8-SIA in the majority of the simulation period. Due to the highest affinity of binding of H3 and H8 with the human receptor, special caution should be exercised regarding any possible outbreak mediated by these subtypes in human populations. However, it is important to acknowledge a limitation inherent to the computational approach; it may hold relative rather than absolute significance. Further research is needed to deepen our understanding of the intricate interplay between HA variants and the host receptor, taking into account the broader context of viral infection dynamics.Communicated by Ramaswamy H. Sarma.

Identification of potential inhibitors targeting Ebola virus VP35 protein: a computational strategy.

Ebola virus (EBOV) poses a severe threat as a highly infectious pathogen, causing devastating hemorrhagic fever in both humans and animals. The EBOV virus VP35 protein plays a crucial role in viral replication and exhibits the ability to suppress the host interferon cascade, leading to immune system depletion. As a potential drug target, VP35 protein inhibition holds promise for combating EBOV. To discover new drug candidates, we employed a computer-aided drug design approach, focusing on compounds capable of inhibiting VP35 protein replication. In this connection, a pharmacophore model was generated using molecular interactions between the VP35 protein and its inhibitor. ZINC and Cambridge database were screened using validated pharmacophore model. Further the compounds were filtered based on Lipinski's rule of five and subjected to MD simulation and relative binding free energy calculation. Six compounds manifest a significant docking score and strong binding interaction towards VP35 protein. MD simulations further confirmed the remarkable stability of these six complexes. Relative binding free energy calculations also showed significant ΔG value in the range of -132.3 and -49.3 kcal/mol. This study paves the way for further optimization of these compounds as potential inhibitors of VP35, facilitating subsequent experimental in vitro studies.Communicated by Ramaswamy H. Sarma.

Chiral chemical absorption property of a cross-linked poly(N-isopropyl acrylamide-co-sodium acrylate) thermoresponsive smart gel.

This investigation leads to the chiral chemical absorption property of a thermoresponsive gel material. D-(+)-α-phenyl ethyl amine was taken as the chiral chemical. The gel material was synthesized by polymerizing 1:1 mole ratio of N-isopropyl acrylamide and Na-acrylate along with methylene bisacrylamide (2 wt.% of total monomer) as a cross-linker using ammonium persulfate as an initiator and N, N, N', N'-tetra-methyl ethylene diamine as an accelerator. The microporous nature of the gel material is observed by scanning electron microscope as well as by surface analysis. It is a pH as well as thermoresponsive gel. The highest gel swelling is observed at around pH 8.2 at room temperature (30 °C). The gel contains carboxylate (-COO(-)) group in this slightly alkaline condition. In the ionic state, the mutual repulsion of the ionic groups helps in swelling the gel. The lower critical solution temperature (LCST) of the gel is observed to be about 38 °C, which is higher than that of poly N-isopropyl acrylamide itself (32 °C). This corroborates with the theory and other reported results that LCST increases with the incorporation of ionic moiety in the cross-linked copolymer. The chiral chemical absorption of the gel material was monitored by measuring circular dichroism of the chiral compound in the presence and absence of gel using a circular dichroism spectropolarimeter (J-810 L) (JASCO International Co., Ltd., Tokyo, Japan). About 18% of D-(+)-α-phenyl ethyl amine is absorbed from its aqueous solution by 0.01 g of dry gel material (particle size: 106-212 µm) at room temperature. The absorption of the chiral compound is reversible with temperature having a sudden jump at LCST (38 °C) of the gel material.

Assessing the utility of remote sensing data to accurately estimate changes in groundwater storage.

Accurate and timely estimates of groundwater storage changes are critical to the sustainable management of aquifers worldwide, but are hindered by the lack of in-situ groundwater measurements in most regions. Hydrologic remote sensing measurements provide a potential pathway to quantify groundwater storage changes by closing the water balance, but the degree to which remote sensing data can accurately estimate groundwater storage changes is unclear. In this study, we quantified groundwater storage changes in California's Central Valley at two spatial scales for the period 2002 through 2020 using remote sensing data and an ensemble water balance method. To evaluate performance, we compared estimates of groundwater storage changes to three independent estimates: GRACE satellite data, groundwater wells and a groundwater flow model. Results suggest evapotranspiration has the highest uncertainty among water balance components, while precipitation has the lowest. We found that remote sensing-based groundwater storage estimates correlated well with independent estimates; annual trends during droughts fall within 15% of trends calculated using wells and groundwater models within the Central Valley. Remote sensing-based estimates also reliably estimated the long-term trend, seasonality, and rate of groundwater depletion during major drought events. Additionally, our study suggests that the proposed method estimate changes in groundwater at sub-annual latencies, which is not currently possible using other methods. The findings have implications for improving the understanding of aquifer dynamics and can inform regional water managers about the status of groundwater systems during droughts.

Managed aquifer recharge implementation criteria to achieve water sustainability.

Depletion of groundwater is accelerated due to an increase in water demand for applications in urbanized areas, agriculture sectors, and energy extraction, and dwindling surface water during changing climate. Managed aquifer recharge (MAR) is one of the several methods that can help achieve long-term water sustainability by increasing the natural recharge of groundwater reservoirs with water from non-traditional supplies such as excess surface water, stormwater, and treated wastewater. Despite the multiple benefits of MAR, the wide-scale implementation of MAR is lacking, partly because of challenges to select the location for MAR implementation and identify the MAR type based on site conditions and needs. In this review, we provide an overview of MAR types with a basic framework to select and implement specific MAR at a site based on water availability and quality, land use, source type, soil, and aquifer properties. Our analysis of 1127 MAR projects shows that MAR has been predominantly implemented in sites with sandy clay loam soil (soil group C) and with access to river water for recharge. Spatial analysis reveals that many regions with depleting water storage have opportunities to implement MAR projects. Analyzing data from 34 studies where stormwater was used for recharge, we show that MAR can remove dissolved organic carbon, most metals, E. coli but not efficient at removing most trace organics, and enterococci. Removal efficiency depends on the type of MAR. In the end, we highlight potential challenges for implementing MAR at a site and additional benefits such as minimizing land subsidence, flood risk, augmenting low dry-season flow, and minimizing salt-water intrusion. These results could help identify locations in the water-stressed regions to implement specific MAR for water sustainability.

Detection of Natural Inhibitors against Human Liver Cancer Cell Lines through QSAR, Molecular Docking and ADMET Studies.

BACKGROUND: Liver cancer is ranked as the fifth most prevalent and third most lethal cancer worldwide. The incidence rates of this cancer are on the rise, and only limited treatment options are available. METHODS: To identify and optimize the inhibitors of liver cancer cell-lines, a QSAR model was developed by using multiple linear regression methods. The robustness of the model was validated through statistical methods and wet-lab experiments. RESULTS: The developed QSAR models yielded high activity descriptor relationship accuracy of 91%, referred to by regression coefficient (r2= 0.91), and a high activity prediction accuracy of 89%. The external predicted (pred_r2) ability of the model was found to be 90%. CONCLUSION: The QSAR study indicates that chemical descriptors such as to measure of electronegative atom count (Epsilon3), atom type count descriptors (MMFF_10), number of a carbon atom connected with four single bonds (SssssCE- index), molecular weight and, number of oxygen atom connected with two aromatic bonds (SaaOE-index) are significantly correlated with anticancer activity. The model, which was validated statistically and through wet-lab experiments, was further used in the virtual screening of potential inhibitors against the liver cancer cell line WRL68. ADMET risk screening, synthetic accessibility, and Lipinski's rule of five are used to filter false positive hits. AfterwardS, to achieve a set of aligned ligand poses and rank the predicted active compounds, docking studies were carried out. The studied compounds and their metabolites were also analyzed for different pharmacokinetics parameters. Finally, a series of compounds was proposed as anticancer agents.

Brevifoliol and its Analogs: A New Class of Anti-tubercular Agents.

Brevifoliol is an abeo-taxane isolated from the Taxus wallichiana needles; eighteen semisynthetic esters derivatives of brevifoliol were prepared by Steglich esterification and screened for their anti-tubercular potential against Mycobacterium tuberculosis H37Ra avirulent strain. The 3- [chloro (7)] and 3, 5-[dinitro (8)] benzoic acid ester derivatives were most active (MIC 25 ug/ml) against the pathogen. Further, in silico docking studies of the active derivative 7 with mycobacterium enzyme inhA (enoyl-ACP reductase) gave the LibDock score of 152.68 and binding energy of -208.62 and formed three hydrogen bonds with SER94, MET98, and SER94. Similarly, when derivative 8 docked with inhA, it gave the LibDock score of 113.55 and binding energy of -175.46 and formed a single hydrogen bond with GLN100 and Pi-interaction with PHE97. On the other hand, the known standard drug isoniazid (INH) gave the LibDock score of 61.63, binding energy of -81.25 and formed one hydrogen bond with ASP148. These molecular docking results and the way of binding pattern indicated that compounds 7 and 8 bound well within the binding pocket of inhA and showed a higher binding affinity than the known drug isoniazid. Additionally, both the derivatives (7 and 8) showed no cytotoxicity, with CC50 195.10 and 111.36, respectively towards the mouse bone marrow-derived macrophages.