In Silico Exploration of Novel Tubulin Inhibitors: A Combination of Docking and Molecular Dynamics Simulations, Pharmacophore Modeling, and Virtual Screening.

Microtubules play a critical role in mitosis and cell division and are regarded as an excellent target for anticancer therapy. Although microtubule-targeting agents have been widely used in the clinical treatment of different human cancers, their clinical application in cancer therapy is limited by both intrinsic and acquired drug resistance and adverse toxicities. In a previous work, we synthesized compound 9IV-c, ((E)-2-(3,4-dimethoxystyryl)-6,7,8-trimethoxy-N-(3,4,5-trimethoxyphenyl)quinoline-4-amine) that showed potent activity against multiple human tumor cell lines, by targeting spindle formation and/or the microtubule network. Accordingly, in this study, to identify potent tubulin inhibitors, at first, molecular docking and molecular dynamics studies of compound 9IV-c were performed into the colchicine binding site of tubulin; then, a pharmacophore model of the 9IV-c-tubulin complex was generated. The pharmacophore model was then validated by Güner-Henry (GH) scoring methods and receiver operating characteristic (ROC) analysis. The IBScreen database was searched by using this pharmacophore model as a screening query. Finally, five retrieved compounds were selected for molecular docking studies. These efforts identified two compounds (b and c) as potent tubulin inhibitors. Investigation of pharmacokinetic properties of these compounds (b and c) and compound 9IV-c displayed that ligand b has better drug characteristics compared to the other two ligands.

3D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Docking Studies for Identification of Tubulin Inhibitors with Potential Anticancer Activity.

In this study, we aimed to develop a pharmacophore-based three-dimensional quantitative structure activity relationship (3D-QSAR) for a set including sixty-two cytotoxic quinolines (1-62) as anticancer agents with tubulin inhibitory activity. A total of 279 pharmacophore hypotheses were generated based on the survival score to build QSAR models. A six-point pharmacophore model (AAARRR.1061) was identified as the best model which consisted of three hydrogen bond acceptors (A) and three aromatic ring (R) features. The model showed a high correlation coefficient (R 2 = 0.865), cross-validation coefficient (Q 2 = 0.718), and F value (72.3). The best pharmacophore model was then validated by the Y-Randomization test and ROC-AUC analysis. The generated 3D contour maps were used to reveal the structure activity relationship of the compounds. The IBScreen database was screened against AAARRR.1061, and after calculating ADMET properties, 10 compounds were selected for further docking study. Molecular docking analysis showed that compound STOCK2S-23597 with the highest docking score (-10.948 kcal/mol) had hydrophobic interactions and can form four hydrogen bonds with active site residues.

New Insight into Vitamins E and K1 as Anti-Quorum-Sensing Agents against Pseudomonas aeruginosa.

Today, antivirulence compounds that attenuate bacterial pathogenicity and have no interference with bacterial viability or growth are introduced as the next generation of antibacterial agents. However, the development of such compounds that can be used by humans is restricted by various factors, including the need for extensive economic investments, the inability of many molecules to penetrate the membrane of Gram-negative bacteria, and unfavorable pharmacological properties and cytotoxicity. Here, we take a new and different look into two frequent supplements, vitamin E and K1, as anti-quorum-sensing agents against Pseudomonas aeruginosa, a pathogen that is hazardous to human life and responsible for several diseases. Both vitamins showed significant anti-biofilm activity (62% and 40.3% reduction by vitamin E and K1, respectively), and the expression of virulence factors, including pyocyanin, pyoverdine, and protease, was significantly inhibited, especially in the presence of vitamin E. Cotreatment of constructed biofilms with these vitamins plus tobramycin significantly reduced the number of bacterial cells sheltered inside the impermeable matrix (71.6% and 69% by a combination of tobramycin and vitamin E or K1, respectively). The in silico studies, besides the similarities of chemical structures, reinforce the possibility that both vitamins act through inhibition of the PqsR protein. This is the first report of the antivirulence and antipathogenic activity of vitamin E and K1 against P. aeruginosa and confirms their potential for further research against other multidrug-resistant bacteria.

The natural phenolic compounds as modulators of NADPH oxidases in hypertension.

BACKGROUND: Hypertension is a major public health problem worldwide. It is an important risk factor for other cardiovascular diseases such as coronary artery disease, stroke, heart failure, atrial fibrillation, peripheral vascular disease, chronic kidney disease, and atherosclerosis. PURPOSE: There is strong evidence that excess ROS-derived NADPH oxidase (NOX) is an important agent in hypertension. It augments blood pressure in the presence of other pro-hypertensive factors such as angiotensin II (Ang II), an important and potent regulator of cardiovascular NADPH oxidase, activates NOX via AT1 receptors. NADPH oxidase, a multi-subunit complex enzyme, is considered as a key source of ROS production in the vasculature. The activation of this enzyme is needed for assembling Rac-1, p40phox, p47phox and p67phox subunits. Since, hypertensive patients need to control blood pressure for their entire life and because drugs and other chemicals often induce adverse effects, the use of natural phenolic compounds which are less toxic and potentially beneficial may be good avenues of addition research in our understand of the underlying mechanism involved in hypertension. This review focused on several natural phenolic compounds as berberine, thymoquinone, catechin, celastrol, apocynin, resveratrol, curcumin, hesperidine and G-hesperidine, and quercetin which are NOX inhibitors. In addition, structure activity relationship of these compounds eventually as the most inhibitors was discussed. METHODS: This comprehensive review is based on pertinent papers by a selective search using relevant keywords that was collected using online search engines and databases such as ScienceDirect, Scopus and PubMed. The literature mainly focusing on natural products with therapeutic efficacies against hypertension via experimental models both in vitro and in vivo was identified. RESULTS: It has been observed that these natural compounds prevent NADPH oxidase expression and ROS production while increasing NO bioavailability. It have been reported that they improve hypertension due to formation of a stable radical with ROS-derived NADPH oxidase and preventing the assembly of NOX subunites. CONCLUSION: It is clear that natural phenolic compounds have some potential inhibitory effect on NADPH oxidase activity. In comparison to other phenolic plant compounds, the structural variability of the flavonoids should off different impacts on oxidative stress in hypertension including inhibition of nadph oxidase and direct scavenging of free radicals.

Effect of Crocin on Antibody Titers to Heat-Shock Protein 27 in Subjects with Metabolic Syndrome.

BACKGROUND: Recent studies have shown that antibody titers to heat shock protein 27 (anti-Hsp27) and serum hs-CRP concentrations are elevated in patients with MetS, and may be associated with an increased risk of cardiovascular disease. Crocin is a natural carotenoid with cardio protective effects. OBJECTIVE: Because of the previous evidence for the beneficial effects of saffron in patients with MetS, this study investigated the effect of supplementation with crocin, the active ingredient of saffron, on serum anti-Hsp27 and hs-CRP in patients with MetS. DESIGN: Sixty subjects with metabolic syndrome were randomized to receive crocin (n=30, 15 mg twice a day) or placebo (n=30, twice a day) for a duration of eight weeks. At the end of study, serum anti-Hsp27 and hs-CRP concentrations were measured and compared between the groups. RESULTS: Serum anti-Hsp27 titers fell by 13% (p>0.05) in the crocin group but it rose in the placebo group by 22% (p>0.05). The magnitude of change in serum anti-Hsp27 titers was not significantly different between the study groups (p = 0.28). In the crocin group, serum anti-Hsp27 changes had a borderline negative correlation with glucose (r= -0.35, p=0.06) and a positive correlation with waist circumference (r=0.39, p=0.035). Serum hs-CRP levels were significantly reduced in both groups but these reductions were not significantly different between the study groups (p = 0.31). CONCLUSION: There was no significant effect of crocin on serum anti-Hsp27 titers in subjects with MetS, but this needs further confirmation in larger-scale trials.

Effect of crocin, a carotenoid from saffron, on plasma cholesteryl ester transfer protein and lipid profile in subjects with metabolic syndrome: A double blind randomized clinical trial.

BACKGROUND: Metabolic syndrome is defined by insulin resistance and a clustering of other cardiovascular risk factors. Crocin is a carotenoid derived from the stigmas of the saffron flower and had previously been shown to affect lipid profile. However, the mechanism for this function is not well understood. The present trial aimed to investigate the possible effect of crocin on plasma levels of cholesteryl ester transfer protein and lipid profile in individuals with metabolic syndrome. METHODS: This was a randomized, double-blind, placebo-controlled, clinical trial consisting of an 8-week treatment with crocin, or placebo tablets between April and June 2014, in the Nutrition Clinic of Ghaem Teaching Hospital, Mashhad, Iran. Participants were randomly assigned to take a 30 mg/day crocin (n = 22) in the intervention group or placebo (n = 22) in the control group. Anthropometric, hematological and biochemical parameters were measured and recorded during pre and post-treatment periods. RESULTS: Whilst plasma cholesteryl ester transfer protein was increased in the group taking the crocin tablet by 27.81% during the trial period (P = 0.013), the difference between the crocin and placebo groups was not significant (P = 0.116). Moreover, the percent changes in cholesterol (P = 0.702), triglyceride (P = 0.080), low-density lipoprotein (LDL) (P = 0.986), high-density lipoprotein (HDL) (P = 0.687) and fasting blood glucose (P = 0.614) did not differ significantly between intervention and control groups. CONCLUSION: Although crocin supplements increased the serum cholesteryl ester transfer protein in patients with metabolic syndrome, this change was not significant between treatment and placebo groups.