Virtual Screening for Potential Inhibitors of NS3 Protein of Zika Virus

Zika virus (ZIKV) is a mosquito borne pathogen, belongs to Flaviviridae family having a positive-sense single-stranded RNA genome, currently known for causing large epidemics in Brazil. Its infection can cause microcephaly, a serious birth defect during pregnancy. The recent outbreak of ZIKV in February 2016 in Brazil realized it as a major health risk, demands an enhanced surveillance and a need to develop novel drugs against ZIKV. Amodiaquine, prochlorperazine, quinacrine, and berberine are few promising drugs approved by Food and Drug Administration against dengue virus which also belong to Flaviviridae family. In this study, we performed molecular docking analysis of these drugs against nonstructural 3 (NS3) protein of ZIKV. The protease activity of NS3 is necessary for viral replication and its prohibition could be considered as a strategy for treatment of ZIKV infection. Amongst these four drugs, berberine has shown highest binding affinity of –5.8 kcal/mol and it is binding around the active site region of the receptor. Based on the properties of berberine, more similar compounds were retrieved from ZINC database and a structure-based virtual screening was carried out by AutoDock Vina in PyRx 0.8. Best 10 novel drug-like compounds were identified and amongst them ZINC53047591 (2-(benzylsulfanyl)-3-cyclohexyl-3H-spiro[benzo[h]quinazoline-5,1'-cyclopentan]-4(6H)-one) was found to interact with NS3 protein with binding energy of –7.1 kcal/mol and formed H-bonds with Ser135 and Asn152 amino acid residues. Observations made in this study may extend an assuring platform for developing anti-viral competitive inhibitors against ZIKV infection.

Effect of chemosensitizers on minimum inhibitory concentrations of fluconazole in candida albicans

To evaluate the effect of chemosensitizers on the in vitro activity of fluconazole against Candida albicans strains. Using Clinical Laboratory Standard Institute method, antifungal activity of fluconazole was determined alone and in combination with 16 chemosensitizers that included verapamil, reserpine, quinine, quinidine, gemfibrozil, lansoprazole, tamoxifen, diltiazem, desipramine, nicardipine, cyclosporine, chlorpromazine, prochlorperazine, promethazine, thioridazine, and trifluoperazine. Further studies were done using double combinations of selected chemosensitizers with fluconazole [28 combinations]. For testing combinations, half of the minimum inhibitory concentration [MIC] of each agent was selected in order to avoid the effect of the drug alone. One reference strain [ATCC90028] and one clinical isolate of C. albicans were used for testing the in vitro activity. Broth dilution method was used to determine the MICs of fluconazole and chemosensitizers. Of the 16 chemosensitizers tested, 3 exhibited in vitro activity by increasing fluconazole susceptibility to 7-fold. The MICs of the reference strain and clinical isolate for fluconazole were 5.5 and 0.55 MU g/ml, respectively, and these were reduced to 0.76 MU g/ml by gemfibrozil, 0.83 MU g/ml by quinine, and 0.76 MU g/ml by chlorpromazine in the reference strain, with MIC reduction to 0.08 MU g/ml by all three chemosensitizers in the clinical isolate. Some double combinations reduced the MIC of fluconazole to 10- to 100-fold, even when the chemosensitizers were not effective alone. The most effective double combinations were those of chlorpromazine with either reserpine or nicardipine

Effects of psychotropic drugs on the thrombin-induced liberation of arachidonate in human platelets

To compare the effects of chlorpromazine [CPZ], prochlorperazine [PCP], trifluoperazine [TFP], clozapine [CLO], haloperidol [HPD], quetiapine [QTP], pimozide [PMZ], and olanzapine [OLP] as well as the tricyclic antidepressants amitriptyline AMI, imipramine IMI, and nortriptyline NTP on thrombin-induced liberation of arachidonic acid AA in platelets. This work was carried out at the Department of Biomedicine, University of Bergen, Norway in 2006-2007. Human platelets pre labelled with [3H] arachidonate were incubated with thrombin in the absence and presence of the drugs, and the amount of free [3H] arachidonate liberated was determined. Myosin light chain [MLC] phosphorylation was determined in [32P] phosphate-labelled platelets after sodium dodecyl sulfate polyacrylamide gel electrophoresis. The effects of the drugs on the molecular area and surface pressure of phospholipid monolayers were determined in the Langmuir apparatus. All drugs reduced arachidonate liberation with the ranking order of increasing potency: OLP. The mechanisms for reduction of arachidonate liberation is thought to interfere with activation of cytosolic phospholipase A2 [cPLA2] by alteration of the PLA2 phospholipid substrate structure in platelet membranes

Antimicrobial potentiality of a phenothiazine group of antipsychotic drug-prochlorperazine.

The antipsychotic drug, prochlorperazine (Pcp), was tested for its antimicrobial efficacy against 103 strains belonging to both gram positive and gram negative bacteria. The drug was found to possess maximum activity against Staphylococcus aureus, Vibrio cholerae and Shigella spp. Pcp was moderately active against E. coli but most of the strains belonging to Bacillus spp, Klebsiella spp, Salmonella spp and Lactobacillus spp were found to be resistant to this drug. The drug was tested for its mode of antibacterial activity against Shigella dysenteriae 1 and it was found to be bacteriostatic in action. In in vivo studies, Pcp offered significant protection to Swiss albino mice at concentrations of 0.75 micro g/g (P < 0.01) and 1.5 microg/g (P < 0.001) body weight when challenged with 50 median lethal dose of Salmonella typhimurium NCTC 74. Thus the result depicts that prochlorperazine may emerge as a strong antimicrobial drug to replace the conventional antibiotics and to overcome the problem of drug resistance.

Cinqüenta anos de medicamentos antipsicóticos em psiquiatria: II - fenotiazinas piperazínicas / Fifty yearts of antipsychotic drugs in psychiatry: II - piperazine phenothiazines

Na iminência de uma nova era na terapêutica psiquiátrica, com a redescoberta da clozapina e a introduçäo de novos antipsicóticos atípicos, é feito um balanço sistemático das substância desenvolvidas nos últimos 50 anos. As substâncias introduzidas até o presente säo reunidas nos grupos-tioxantênicos com estrutura aparentada às fenotiazinas), tioxantenos, butirofenonas, difenilbutilpiperidinas, benzamidas, indóis, dibenzoxazepinas - e nos grupos químicos mais recentes - dibenzodiazepinas, benzisoxazólicos, tienobenzodiazepinas, dibenzotiazepinas, benzisotiazólicos, didroindolonas, imidazolidinonas -, além de compostos ainda em desenvolvimento. Neste artigo, o segundo da série concebida com esta finalidade, säo examinados os derivados fenotiazínicos com cadeia lateral piperazínica, carfenazina, clorimpifenina, dixirazina, flufenazina, metofenazina, oxaflumazina, perazina, perfenazina, proclorperazina, tietilperazina, tiopropazato, tioproperazina e trifluperazina. Com base em bibliografia básica específica, säo discutidos aspectos técnicos e revisado o conhecimento cientíco acumulado através da experimentaçäo e da utilizaçäo clínica destes compostos, desde seu lançamento até a presente data, com informaçöes sistemáticas sobre fórmula estrutural, fórmula molecular, nomes químicos, nomes fantasia e códigos de cada composto, além de dados sobre sua eventual comercializaçäo no país

Evaluation of prochlorperazine buccal tablets (Bukatel) and metoclopramide oral tablets in the treatment of acute emesis.

The dizziness associated with vertiginous disorders is often accompanied with nausea and/or vomiting. Antiemetic effect of prochlorperazine (PCZ) is diminished by its low bioavailability owing to a significant gastric and hepatic first pass effect. This effect could be further diminished by likelihood of regurgitation of nauseating patients further limiting the therapeutic effect of oral PCZ. A buccal preparation achieves higher plasma concentrations through direct systemic absorption. In this study buccal prochlorperazine (Bukatel) was compared for its efficacy and tolerability with commonly used metoclopramide. Bukatel was well tolerated and well rated by both patients and investigators with no adverse effects on buccal mucosa and causing less drowsiness and sedation. Results indicate that Bukatel is safe and effective for the treatment of nausea and/or vomiting in patients suffering from vertiginous disorders and could be safely and strongly recommended as an alternative to less bioavailable and indiscriminately used oral metoclopramide tablets.

Comparison of ondansetron [5-HT3 antagonist] versus prochlorperazine to prevent postoperative nausea and vomiting

In a placebo-controlled study, the efficacy of intravenous Ondansetron 4 mg administered prior have been compared to induction of anesthesia versus intramuscular prochlorperazin given as 10 mg starting prior to induction of anesthesia. This study was performed to compare the incidence of nausea and emesis during the 24-hour postoperative period in women between the age of 18 and 60 years undergoing gynecological or gastrointestinal operations with general anesthesia. Intravenous Ondansetron tested versus prochlorperazine was significantly more effective than placebo. The percentages of patients who experienced postoperative emesis following surgery until 24 hours after recovery were 33%, 48%, and 66%, respectively

New data on the use of antidepressant and disinhibitory drugs

The authors studied the new findings concerning the utilization of the antidepressants and the disinhibitory drugs, by taking into consideration their mode of usage and their pharmacokinetics. In the first part the authors demonstrated the utility of the pharmacokinetic studies and plasmatic percentages of the antidepressants to allow for a better utilization and a more therapeutic efficiency. Moreover they put emphasis on the indications of antidepressants according to such or such target symptom. In the second part of the account the authors indicated the disinhibitory effect of antidepressants that can be at advantage in certain deficitary forms of schizophrenia. Certain products [sulpiride] and certain original formulas [carpipramine] have specific disinhibitory actions

Effects of tranquillising, antidepressant and central nervous system stimulant drugs on the gamma-aminobutyric acid (GABA) level of rat brain.

The level of y-aminobutyric acid (GABA) was determined in the brain of rats 1 hr. after i.p. injection of chlorpromazine, prochlorperazine, diazepam, trimipramine, methamphetamine and nikethamide. Diazepam increased, and, trimipramine and amphetamine decreased the brain GABA level over wide dose ranges. Low doses of chlorpromazine and prochlorperazine increased but high doses of the drugs reduced the GABA level. Low doses of nikethamide reduced whereas high doses increased the level of GABA. The effects of the drugs have been discussed in relation to the brain GABA level.