Drug repurposing for SARS-CoV-2 main protease: Molecular docking and molecular dynamics investigations

The current novel corona virus illness (COVID-19) is a developing viral disease that was discovered in 2019. There is currently no viable therapeutic strategy for this illness management. Because traditional medication development and discovery has lagged behind the threat of emerging and re-emerging illnesses like Ebola, MERS-CoV, and, more recently, SARS-CoV-2. Drug developers began to consider drug repurposing (or repositioning) as a viable option to the more traditional drug development method. The goal of drug repurposing is to uncover new uses for an approved or investigational medicine that aren't related to its original use. The main benefits of this strategy are that there is less developmental risk and that it takes less time because the safety and pharmacologic requirements are met. The main protease (Mpro) of corona viruses is one of the well-studied and appealing therapeutic targets. As a result, the current research examines the molecular docking of Mpro (PDB ID: 5R81) conjugated repurposed drugs. 12,432 approved drugs were collected from ChEMBL and drugbank libraries, and docked separately into the receptor grid created on 5R81, using the three phases of molecular docking including high throughput virtual screening (HTVS), standard precision (SP), and extra precision (XP). Based on docking scores and MM-GBSA binding free energy calculation, top three drugs (kanamycin, sulfinalol and carvedilol) were chosen for further analyses for molecular dynamic simulations.     

Photochemical response of the scleractinian coral Stylophora pistillata to some sunscreen ingredients

Coral Reefs - Ultraviolet (UV) filters and preservatives, which are common constituents of sunscreens and other cosmetics, are reported as a threat for coastal coral reef ecosystems; however, few...     

Synthesis, antimicrobial activity and conformational analysis of novel substituted pyridines: BF(3)-promoted reaction of hydrazine with 2-alkoxy pyridines

Some new 2-alkoxy-3-cyano-4,6-diarylpyridines 3,4 were synthesized by condensation of different alpha,beta-unsaturated ketones 1 with malononitrile 2, followed by cyclization in sodium alkoxide/alcohol system. Lewis acid-catalyzed reaction of 4 with hydrazine afforded the corresponding 1H-pyrazolo[3,4-b]pyridines 5. The potency of the results as antimicrobial agents has been evaluated. The structure of the newly prepared compounds was assessed by microanalysis, IR and NMR spectra. Molecular mechanics (MM2) and semiemperical (AM1) molecular orbital calculations have been performed for the most biologically active compounds 5b and c to get insight into their molecular structures and to learn more about their stable molecular conformations.     

Regulation of dendritic branching and filopodia formation in hippocampal neurons by specific acylated protein motifs

Although neuronal axons and dendrites with their associated filopodia and spines exhibit a profound cell polarity, the mechanism by which they develop is largely unknown. Here, we demonstrate that specific palmitoylated protein motifs, characterized by two adjacent cysteines and nearby basic residues, are sufficient to induce filopodial extensions in heterologous cells and to increase the number of filopodia and the branching of dendrites and axons in neurons. Such motifs are present at the N-terminus of GAP-43 and the C-terminus of paralemmin, two neuronal proteins implicated in cytoskeletal organization and filopodial outgrowth. Filopodia induction is blocked by mutations of the palmitoylated sites or by treatment with 2-bromopalmitate, an agent that inhibits protein palmitoylation. Moreover, overexpression of a constitutively active form of ARF6, a GTPase that regulates membrane cycling and dendritic branching reversed the effects of the acylated protein motifs. Filopodia induction by the specific palmitoylated motifs was also reduced upon overexpression of a dominant negative form of the GTPase cdc42. These results demonstrate that select dually lipidated protein motifs trigger changes in the development and growth of neuronal processes.     

Endoscopic ultrasound-guided fine needle aspiration of the pancreas. Diagnostic utility and accuracy

OBJECTIVE: Endoscopic ultrasound-guided fine needle aspiration biopsy (EUS-FNAB) is regarded as a safe and reliable procedure for diagnosing and staging of pancreatic neoplasms. This study retrospectively evaluated both the diagnostic utility and accuracy of pancreatic EUS-FNABs and potential cytologic pitfalls when using Diff-Quik stain for on-site evaluation. STUDY DESIGN: Pancreatic EUS-FNABs performed between 1995 and 1998 were identified from the files of the Department of Pathology. All patients were studied via a linear-array ultrasound endoscope with an FNAB device. Immediate evaluation of the specimen by a pathologist using air-dried slides and Diff-Quik stain was done on all cases. An average of five passes (range, three to nine) were performed. Five cytologic categories were identified: nondiagnostic, benign, atypical, suspicious and malignant. EUS disease staging, histologic correlation and clinical follow-up were reviewed. RESULTS: Sixty-nine consecutive pancreative FNABs were evaluated in the study period. The patients comprised 38 females and 31 males with a mean age of 65 years (range, 36-83). Histologic correlation was available on 40 patients, and follow-up was available on the remaining 29. The cytologic diagnoses included: 31 malignant, 8 suspicious, 6 atypical, 20 benign and 4 nondiagnostic. Forty-three cases were true positive, 9 were true negative, 2 were false positive, and 11 were false negative. The overall sensitivity was 80% and specificity was 82%. CONCLUSION: The study showed that cytologic evaluation of pancreatic EUS-FNABs has 80% sensitivity and 82% specificity. False negative diagnosis was usually due to sampling error. A nondiagnostic cytologic diagnosis should be rendered in the absence of adequate sampling of a lesion. On-site cytologic evaluation of EUS-FNABs aids in guaranteeing specimen adequacy, and the pathologist should be trained to evaluate Diff-Quik-stained samples.     

Separation and purification of Echis coloratus venom and some biological and biochemical effects of the proteins

Crude venom of Echis coloratus was separated into seven protein fractions using 7% preparative native polyacrylamide gel electrophoresis. The effect of crude venom and seven venom protein fractions (F1-F7) from Echis coloratus on key metabolic activities of fibroblast cultures was investigated. Confluent cultures were incubated with the venom proteins for 3 h at 37 degrees C. The specific activity of phosphofructokinase, was significantly lowered upon incubation with the crude venom and with fractions 2, 3, 4 and 6. Citrate synthase activity was significantly lowered by the crude venom and by fractions 2 and 3. Glycogen phosphorylase activity was significantly increased by the crude venom and by fractions 2, 3, 4 and 6 leading to a significant concurrent drop in glycogen content. Creatine kinase activity was significantly increased by the crude venom and by fractions 3, 4, 5 and 6. Cellular ATP levels rose significantly upon incubation with the crude venom and with fractions 3, 4, 5 and 6. Incubation of cell sonicates with all the venom proteins did not significantly alter the activity or content of any of the studied parameters.     

Effect of cadmium and zinc ethanolamine complexes on rat brain monoamine oxidase-B activity in vitro

Monoamine oxidase-B (MAO-B) from rat brain was inhibited strongly by the prepared cadmium and zinc ethanolamine complexes obtained from their sulphate and chloride salts. The inhibition of MAO-B by these complexes was time-dependent and fully reversible after dilution and sedimentation. In vitro, the cadmium ethanolamine complexes were more potent at inhibiting MAO-B than the zinc complexes. The inhibitory effect of these complexes follow the order: TEA>DEA>MEA, due to the alkyl residues and steric effect properties. The inhibition of MAO-B by cadmium and zinc ethanolamine complexes was a noncompetitive type. The K(i) values were calculated. The influence of the complexes on the activity of MAO-B was rather evaluated. It decreased the MAO-B activity. The IC(50) values of the two potent cadmium and zinc triethanolamine complexes on MAO-B were evaluated indicating that the complexes were tightly binding, but reversible inhibitors for MAO-B. In general, these systems may be used for preventing some neurodegenerative diseases.     

Heavy metal concentrations in the breast milk of Saudi women

Lead, cadmium, and mercury concentrations were determined in breast milk of Saudi lactating mothers from Riyadh and Al-Ehssa regions in Saudi Arabia who were not occupationally exposed. The mean levels for cadmium, lead, and mercury were 1.732 μg/L, 31.671 μg/L, and 3.100 μg/L, respectively. In contrast to mercury, mothers living in the Al-Ehssa region had significantly higher cadmium and lead concentrations in their breast milk than those in the Riyadh region. The estimated weekly intakes of cadmium, lead, and mercury of breast-fed infants in this study were in some cases higher than the Provisional Tolerance Weekly Intake (PTWI) recommended by FAO/WHO, which pose a threat to their health. This necessitates the urgent need to undertake a comprehensive study to determine the sources of exposure to these heavy metals. Breast-feeding is of great benefical value for the infant’s development; therefore, efforts should be made to prevent its contamination with environmental pollutants.     

Design and synthesis of acyclic nucleoside analogs with chlorinated imidazo[1,2-a]pyridine bases

A series of acyclic C-nucleoside analogs of 2,6-dichloro- and 2,6,7-trichloroimidazo[1,2-a]pyridine were synthesized and tested for antiviral activity. The appropriate hydroxymethyl-substituted heterocycles were treated successively with thionyl chloride, an appropriate nucleophile, then diisopropylethylamine to obtain the desired acyclic nucleoside analogs. These compounds were evaluated for activity against human cytomegalovirus and herpes simplex virus, type 1. Two of the dichloro analogs, but none of the trichloro analogs demonstrated slight antiviral activity (IC50's = 20-45 microM) at non-cytotoxic concentrations.