DFT and Molecular Docking Studies of a Set of Non-Steroidal Anti-Inflammatory Drugs: Propionic Acid Derivatives

Inflammation is the body’s defense mechanism to eradicate the spread of injurious agents in the affected mammalian tissues with a number of cellular mediators. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used drugs worldwide in such situations. The mode of action of the non-steroid anti-inflammatory drugs (NSAIDs) is attributed primarily to the inhibition of prostaglandin (PG) synthesis, and more specifically, to the inhibition of the COX enzyme system. This work can be considered as an effort to gain a deeper insight into the physiochemical properties of a few well-known NSAIDs namely; ketoprofen, fenoprofen, flurbiprofen and ibuprofen. A quantum computational approach was used to predict geometry, molecular electrostatic potential (MESP), polarizability, hyperpolarizability and molecular docking study of all selected NSAIDs with human COX-1 and COX-2 enzymes were done to predict the most active drug among the four and to demonstrate good selectivity profile with COX enzymes

Analisis Teoritik Aktivitas Antioksidan, Toksisitas, Skor Obat Dan Doking Molekuler Senyawa Kaempferol Dan Turunannya

The potential of kaempferol and its derivatives namely kaempferol, 8-prenyl kaempferol, rhamnocitrin and kaempferide as cancer drug candidates was investigated through reactivity parameters, antioxidant activity, pKa value, toxicity, drug score, reaction with radicals, and molecular docking. This study studied the mechanism of antioxidant activity through (Density Functional Theory) DFT/ (Beckee-3-Lee Yang Parr) B3LYP/6-31G method in the gas phase. The Quantitative Structure-Activity Relationship (QSAR) of compounds with antioxidant activity and toxicity was analyzed based on a multilinear regression equation. The results showed the reactivity of kaempferol derivatives molecules was ordered as follows: 8-prenilkaempferol > Kaempferide > Kaempferol > Rhamnocitrin. The antioxidant reaction mechanism for OH bond breaking to produce H● and ArO● is easier to occur in the Single Electron Transfer - Proton Transfer (SET-PT) mechanism due to the total energy generated by the smaller Ionization Potential (IP) + Proton Dissociation Enthalpy (PDE). The pKa analysis shows that the pKa of kaempferol and its derivatives are close to the pKa of blood, so they can be declared soluble in blood. Determination of the toxicity of kaempferol derivatives showed that kaempferol derivative (8-prenyl kaempferol) meets the Lipinski rule as a drug candidate, is not tumour genetic, non-irritating and does not cause gene mutation and meets the drug score of 0.585. Multilinear regression analysis found that the Inhibition Concentration 50% (IC50) values of kaempferol and its derivatives were theoretically the same as experimentally. The pharmacophore study found that the compound that has the best interaction with the receptor of Human Papillomavirus (HPV) type 11 L1 (2R5K) is the 8-prenilkaempferol compound with the highest docking energy of -8.0056 kJ/mol. The reactivity of the molecule to ROS (Reactive Oxygen Species) and RNS (Reactive Nitrogen Species) in the gas phase shows the phenolic OH group is reactive and can react well with ●OH and ●NO. The results showed that kaempferol compounds are potential free radical scavengers at the H termination at the C4’ position compared to the C3 position and are good antioxidants. In conclusion, kaempferol molecules and their derivatives have the potential to be used as drug candidates. Keywords: Kaempferol, DFT, Antioxidant, Toxicity, Molecular docking

Studies on Histamine H2-Receptor Antagonists by Using Density Functional Theory

Density functional theory (DFT) is a quantum mechanical approach used to investigate the electronic structure (principally the ground state) of many-body systems, in particular atoms, molecules, and the condensed phases. In this work, we have used DFT/B3LYP/6-31+G(d) level of theory to get insight into the molecular geometry and thermochemical properties of histamine H2-receptor antagonists. Histamine H2-receptor antagonists or H2 blockers are a group of pharmaceutical ingredients that reduce the amount of acid produced by the cells in the lining of the stomach. The potential H2 blockers include cimetidine, famotidine, nizatidine, and ranitidine. The detailed theoretical investigation on the listed H2 blockers in terms of their thermochemical parameters and global descriptive parameters revealed that, though famotidine is the best among them with highest Gibbs free energy, nizatidine showed higher biological activity with high softness, low hardness, and high electrophilicity index. The theoretical vibrational spectra of these four Histamine H2-receptor antagonists were analyzed and the infrared spectra of nizatidine was compared with the experimental IR spectra, and found to be good agreement with the experimental values. Further, frontier molecular orbitals especially the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) were determined and the activation energy of the selected samples were calculated. In addition to this, the amorphisation technique were employed to enhance the solubility and bio availability of the best biologically active H2 blocker nizatidine using broadband dielectric spectroscopy

Anti-angiogenic and toxicity effects of Derris trifoliata extract in zebrafish embryo

Introduction: Derris trifoliata has been traditionally used as folk for the treatment of , rheumatic joints, diarrhoea, and dysmenorrhea, and rotenoids isolated from the plant have shown to exhibit anti-cancer properties. This study aimed to assess the toxicity effects and antiangiogenic activity of extract of Derris trifoliata on zebrafish embryo model. Materials and Methods: Zebrafihs embryos were treated with aqueous extract of Derris Trifoliata to evaluate its effects on angiogenesis and zebrafish-toxicity. Angiogenic response was analyzed using whole-mount alkaline phosphatase (AP) vessel staining on 72 hours post fertilization (hpf) zebrafish embryos. Results: 1.0 mg/ml concentration was toxic to zebrafish embryos and embryos exposed to concentrations at 0.5 mg/ml and below showed some malformations. Derris trifoliata aqueous extract also showed some anti-angiogenic activity in vivo in the zebrafish embryo model wereby at high concentration inhibited vessel formation in zebrafish embryo. Conclusions: The anti-angiogenic response of extract of Derris trifoliata in zebrafish in vivo model suggest its therapeutic potential as anti-cancer agent

Identifying novel drugs for the treatment of rhabdomyosarcoma

Rhabdomyosarcoma (RMS) forms in skeletal muscle and is the most common soft tissue sarcoma in children and adolescents. Current treatment is associated with debilitating side effects and treatment outcomes for patients with metastatic disease are dismal. Other than a need for alternative and more effective therapies there is also a growing appreciation for the need to understand the molecular underpinnings of RMS with the aim of identifying, in part, novel targets to develop highly specific and effective treatments with negligible adverse effects. The aim of this study was to identify novel drugs for the treatment of the two major RMS subtypes viz alveolar (ARMS) and embryonal (ERMS) RMS and to do so it adopted a two-pronged approach. Firstly, a novel binuclear palladacycle, AJ-5, was investigated for its anti-cancer activity and its mechanism(s) of action in RMS cells. The second approach involved a target-based drug repurposing strategy where a library of FDA-approved drugs was screened to identify leads that were able to negatively regulate the oncogenic TBX2 and TBX3 transcription factors that are known drivers of RMS. The binuclear palladacycle, AJ-5, was recently shown to exert potent cytotoxicity in melanoma and breast cancer and to present with negligible adverse effects in mice. To investigate the anti-cancer activity of AJ-5 in RMS cells, MTT assays were firstly performed in ERMS and ARMS as well as 'normal' cells. IC50 values determined from these experiments showed values of ≤ 0.2μM for the RMS cells and a favourable selectivity index of > 2. Clonogenic and migration assays showed that AJ-5 inhibited the ability of RMS cells to survive and migrate respectively. Western blotting revealed that AJ-5 induced levels of key DNA damage response proteins (γH2AX, p-ATM and p-Chk2) and the p38/MAPK stress pathway. This correlated with an upregulation of p21 and a G1 cell cycle arrest. Annexin V-FITC/propidium iodide staining revealed that AJ-5 induced apoptotic and necrotic cell death. Apoptosis was confirmed by the detection of cleaved PARP and increased levels and activity of cleaved caspases-3, -7, -8 and -9. Increased levels of necroptotic markers p-RIP3 and p-MLKL and inhibition of necroptosis with necrostatin-1 with a corresponding significant increase in cell viability suggests that AJ-5 is also capable of triggering a form of programmed necrosis. Furthermore, AJ-5 reduced autophagic flux as shown by reduced LC3II accumulation in the presence of bafilomycin A1, and a significant reduction in autophagosome flux J. Pharmacokinetic studies in mice show that AJ-5 has a promising half-life and that its volume of distribution is high, its clearance low and its intraperitoneal absorption is good. With the intention of improving the drug-like properties of AJ-5, specifically its water solubility, a derivative of AJ-5, BTC2, was synthesised and identified to display comparable anti-cancer activity against ERMS and ARMS cells. Together these findings suggest that AJ-5 and BTC2 may be effective chemotherapeutics with a desirable and novel mechanism of action for treating drug resistant and advanced RMS. The highly homologous T-box transcription factors TBX2 and TBX3 have both been implicated as key drivers of RMS and they have been identified as novel therapeutic targets for the treatment of this sarcoma subtype. Indeed, TBX2 or TBX3 overexpression in normal myoblasts inhibits muscle differentiation and overexpression and knock-down cell culture and mouse models show that RMS cells are addicted to them for their cancer phenotype. However, targeting transcription factors is notoriously challenging because unlike enzymes they do not have catalytic activity and deep binding pockets to which small molecule inhibitors can be designed which is further exacerbated by the length of time and costs associated with de novo drug development. Therefore, this study adopted a novel strategy to circumvent these challenges by combining a drug repurposing with a targeted approach to TBX2/3. Briefly, a high throughput cell-based immunofluorescence screen was designed and conducted to identify FDA-approved drugs that could negatively regulate TBX2 and/or TBX3 protein levels or nuclear localisation. Cells were engineered to express induced exogenous FLAG-tagged TBX2 and TBX3 using a Tet-On system and they were screened with the Pharmakon 1600 drug library at a concentration of 10μM. 'Hits' were identified by z-scores and amongst these, niclosamide, piroctone olamine and pyrvinium pamoate were validated to be potent inhibitors of TBX2/3 and were shown to display anti-cancer activity in RMS. These drugs have the potential to be repurposed for the treatment of RMS and other TBX2/3 driven cancers either as single agents or in combination with currently used chemotherapeutics

Sewage sludge heavy metal analysis and agricultural prospects for Fiji

Insoluble residues produced in Waste Water Treatment Plants (WWTP) as by products are known as sewage sludge (SS). Land application of SS, particularly in agricultural lands, is becoming an alternative disposal method in Fiji. However, currently there is no legislative framework governing its use. SS together with its high nutrient and organic matter contents, constitutes some undesired pollutants such as heavy metals, which may limit its extensive use. The focus of this study therefore was to determine the total concentrations of Pb, Zn, Cd, Cu, Cr, Ni and Mn in the SS produced at the Kinoya WWTP (Fiji) and in the non-fertile soil amended with the SS at 20, 40, 60, 80% application rates and in the control (100% Soil). The bioavailable heavy metals were also determined as it depicts the true extent of metal contamination. The treatment mixtures were then used to cultivate cabbage plants in which the total heavy metal uptake was investigated. Total Zn (695.6 mg/kg) was present in the highest amounts in the 100% SS (control), followed by Pb (370.9 mg/kg), Mn (35.0 mg/kg), Cu (65.5 mg/kg), Cr (20.5 mg/kg) and finally Cd (13.5 mg/kg) and hence a similar trend was seen in all treatment mixtures. The potential mobility of sludgeborne heavy metals can be classified as Ni > Cu > Cd > Zn > Mn > Cr > Pb. Total metal uptake in plant leaves and stems showed only the bioavailable metals Cu, Cd, Zn and Mn, with maximum uptake occurring in the leaves. Ni, despite being highly mobile was not detected, due to minute concentrations in the SS treatments. Optimum growth occurred in the 20 and 40% SS treatments. However maximum Cu and Mn uptake occurred in the 40% SS treatment thereby making the 20% treatment the most feasible. Furthermore the total and bioavailable metal concentrations observed were within the safe and permitted limits of the EEC and USEPA legislations

Continuing professional development - challenge for professional organization

Professions, as one of key sectors of social systems, bear a leading role in the existing social work organization. Free professions take up a special place and significance, all the way from Roman artes liberales to our times. Pharmaceutical profession, as one of the oldest, led by ethical principles, is regulated by postulates accepted by the profession members, and in modern times established through legislations. Typical determinants of the regulated professions, which also refer to pharmacists, as chamber members, are as follows: following ethical principles, specific skills and knowledge, professional development, autonomy at work, continuing improvement, competencies development, professional associations, licensing