Putative Anti-Cancer Drug Candidate Targeting the 'PLK-1-Polo-Box Domain' by High Throughput Virtual Screening: A Computational Drug Design Study.

Cancer continues to remain a disease of scientific concern. Significant interest in targeting the Polo-Box-Domain (PBD) of Polo-like-kinase-1 (PLK-1) by novel ligands has arisen. The 'cleft' constituted by amino acid residues W414, H538, and K540 is the traditional target of PLK-1-PBD-inhibitors. However, this 'cleft' is merely a small part of the larger 'Y'-shaped cavity present therein. The objective of this study was to discover inhibitors of the PLK-1-PBD precisely directed against its trimodular 'Y'-pocket. High-throughput structure-based virtual screening (SBVS) of more than 5 million ligands against the aforementioned PLK-1 'Y'-pocket was performed. The SBVS hits were successively subjected to pass through various filters: VINA score ranking, toxicity checker, 'Special Criteria'-filtration, holistic tri-modular 'Y'-pocket interaction check, drug-likeness filters, and medicinal chemistry filters. Accordingly, we arrived at a single top ligand, 'SHAZ-i.' The top ligand, 3-{2-[(2-Methyl-2-propanyl)sulfonyl]phenyl}-5-phenyl-1,2-oxazole-4-carboxamide, displayed a robust interaction with the target crevice through 15 amino acid residues, an acceptable ΔG value of -7.8 kcal/mol, and a favorable pharmacokinetic profile with no adverse effects on humans. Hence, 3-{2-[(2-Methyl-2-propanyl)sulfonyl]phenyl}-5-phenyl-1,2-oxazole-4-carboxamide could emerge as a potent PLK-1-PBD inhibitor or might act as a 'seed' molecule for design of future inhibitors with a closely related backbone structure.

Hepato-protective effect of Allium sativum against immobilization stress in rats.

The purpose of the current study was to examine immobilization stress-induced antioxidant defense changes and estimation of the antioxidant potential of pre and post stress treatment of aqueous garlic extract in rat's liver. For this purpose, male Albino Wistar rats were treated with aqueous garlic extract both pre and after 6 h of immobilization stress. Pro-oxidant status of rat liver was evaluated by determining the levels of reduced glutathione (GSH), thiobarbituric acid reactive substances (TBARS), aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), glucose, uric acid and the activities of super oxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST). In response to 6 h of immobilization stress a significant rise in the level of above mentioned liver enzymes were recorded. However, SOD, CAT and GST enzymatic activities showed a sharp decline. The extract treatment before and after stress, almost reverted the activities of studied biochemical parameters towards their control values. Current study highlighted the antioxidant potential of garlic extracts. Based on our study, we recommend the use of garlic extract as nutritional supplement for combating oxidative stress induced damage.

Mutagenic, antioxidant and wound healing properties of Aloe vera.

ETHNOPHARMACOLOGICAL RELEVANCE: Aloe vera is a widely used medicinal plant for its various biological activities. This study evaluate possible mutagenic and healing effects of the aqueous extract of A. vera (AEAV) in mice and its oxidant/antioxidant potential in different proficient and deficient Saccharomyces cerevisiae strains. MATERIAL AND METHODS: The AEAV was topically treated on the wounded skin surface of male albino mice at doses of 10 and 50 mg/kg for seven successive days. The control group was similarly treated with 0.9% NaCl solution. For oxidative/anti-oxidative evaluation, both proficient and deficient strains of S. cerevisiae [cytoplasmic and mitochondrial superoxide dismutase mutant (SOD: Sod1Δ and Sod2Δ), cytoplasmic catalase mutant (CAT: Cat1Δ)], two double defective mutants of Sod1 and Sod2 and Sod1 and Cat1 genes along with a wild-type strains were used. RESULTS: The healing property of AEAV was observed at the dose of 50 mg/kg but at the same dose it showed mutagenic and cytotoxic effects in peripheral blood. AEAV did not produce the oxidizing effect, except in the mutated CAT strain at highest concentration (50 mg/kg). CONCLUSION: The high concentration of AEAV showed mutagenicity and cytotoxicity. Beside, the healing capacity is believed to be due to its anti-oxidative defense mechanism.

Silver nanoparticles from leaf extract of Mentha piperita: Eco-friendly synthesis and effect on acetylcholinesterase activity.

Silver nanoparticles (AgNPs) have been used in various medicinal and commercial products because of their exceptional anti-microbial and anti-odor properties. On the other hand, increased commercialization of AgNPs containing products has led to its release into the environment. Thus, studies are needed to assess their impact on the environment as well as on human body. Several reports have shown that AgNPs could cause some serious neurotoxic effects. Most of these studies have been performed using chemically synthesized AgNPs. In contrast, green nanoparticles are usually considered safer than their chemically synthesized counterparts. Accordingly, in this research work, we have assessed the effect of AgNPs synthesized from aqueous-leaf-extract of Mentha piperita on one of the most important neurological enzymes i.e. acetylcholinesterase (AChE) to predict its neurotoxicity. M. piperita synthesized AgNPs were subjected to characterization by UV-visible-spectrometry, Scanning Electron-Microscopy as well as Transmission Electron-Microscopy. Here, the size of the AgNPs was found to be 35 nm with spherical shape. These AgNPs showed concentration-dependent inhibitory-effect on the AChE enzyme-activity displaying an IC50 of 150 nM. Further, kinetic analysis showed mixed type of inhibition, which means that AgNPs were capable of binding to both the free enzyme (AChE) and to the enzyme-substrate (AChE-acetylcholine) complex. These results suggest that even green synthesized AgNPs might cause neurotoxicity via inhibiting AChE activity. However, more studies are needed to elucidate the exact mechanism of neurotoxicity by AgNPs. Nevertheless, we could safely state that the present study provides relevant preliminary information regarding neurotoxicity of green synthesized AgNPs.

Synthesis and Characterization of Cefotaxime Conjugated Gold Nanoparticles and Their Use to Target Drug-Resistant CTX-M-Producing Bacterial Pathogens.

Multidrug-resistance due to "ß lactamases having the expanded spectrum" (ESBLs) in members of Enterobacteriaceae is a matter of continued clinical concern. CTX-M is among the most common ESBLs in Enterobacteriaceae family. In the present study, a nanoformulation of cefotaxime was prepared using gold nanoparticles to combat drug-resistance in ESBL producing strains. Here, two CTX-M-15 positive cefotaxime resistant bacterial strains (i.e., one Escherichia coli and one Klebsiella pneumoniae strain) were used for testing the efficacy of "cefotaxime loaded gold-nanoparticles." Bromelain was used for both reduction and capping in the process of synthesis of gold-nanoparticles. Thereafter, cefotaxime was conjugated onto it with the help of activator 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide. For characterization of both unconjugated and cefotaxime conjugated gold nanoparticles; UV-Visible spectroscopy, Scanning, and Transmission type Electron Microscopy methods accompanied with Dynamic Light Scattering were used. We used agar diffusion method plus microbroth-dilution method for the estimation of the antibacterial-activity and determination of minimum inhibitory concentration or MIC values, respectively. MIC values of cefotaxime loaded gold nanoparticles against E. coli and K. pneumoniae were obtained as 1.009 and 2.018 mg/L, respectively. These bacterial strains were completely resistant to cefotaxime alone. These results reinforce the utility of conjugating an old unresponsive antibiotic with gold nanoparticles to restore its efficacy against otherwise resistant bacterial pathogens. J. Cell. Biochem. 118: 2802-2808, 2017. © 2017 Wiley Periodicals, Inc.

Comparative Inhibition Study of Compounds Identified in the Methanolic Extract of Apamarga Kshara Against Trichomonas vaginalis Carbamate Kinase (TvCK): An Enzoinformatics Approach.

In the present study, we have identified ten compounds, namely dodecanol acid, myristic acid, neophytadiene, palmitic acid, heptadecanoic acid, linoleic acid, elaidic acid, 3-7-dimethyl acid, stearic acid and methyl eicos acid, of the methanolic extract of Apamarga Kshara by GC-MS analysis. Apamarga Kshara has been reported to be active against cervical erosion. Major causal organism for cervical erosion is Trichomonas vaginalis. However, there is a paucity of information about the mechanism of action and inhibitory effect of the biologically active natural compounds presented in A. Kshara against this organism (T. vaginalis). Therefore, present investigation was conducted to observe possible interactions of these compounds on T. vaginalis carbamate kinase using molecular docking software 'AutoDock 4.2.' Identification of the amino acid residues crucial for the interaction between T. vaginalis carbamate kinase and these natural compounds is of due scientific interest. The study will aid in efficacious and safe clinical use of the above-mentioned compounds.

Antimicrobial activity of five herbal extracts against multi drug resistant (MDR) strains of bacteria and fungus of clinical origin.

Antimicrobial activities of the crude ethanolic extracts of five plants were screened against multidrug resistant (MDR) strains of Escherichia coli, Klebsiella pneumoniae and Candida albicans. ATCC strains of Streptococcus mutans, Staphylococcus aureus, Enterococcus faecalis, Streptococcus bovis, Pseudimonas aeruginosa, Salmonella typhimurium, Escherichia coli, Klebsiella pneumoniae and Candida albicans were also tested. The strains that showed resistance against the maximum number of antibiotics tested were selected for an antibacterial assay. The MDR strains were sensitive to the antimicrobial activity of Acacia nilotica, Syzygium aromaticum and Cinnamum zeylanicum, whereas they exhibited strong resistance to the extracts of Terminalia arjuna and Eucalyptus globulus. Community-acquired infections showed higher sensitivity than the nosocomial infections against these extracts. The most potent antimicrobial plant was A. nilotica (MIC range 9.75-313 microg/ml), whereas other crude plant extracts studied in this report were found to exhibit higher MIC values than A. nilotica against community acquired as well as nosocomial infection. This study concludes that A. nilotica, C. zeylanicum and S. aromaticum can be used against multidrug resistant microbes causing nosocomial and community acquired infections.