Open Access Original Research Article

Study of Molecular Docking, Physicochemical and Pharmacokinetic Properties of GSK-3β Inhibitors

Leide C. S. Picanço, Leandro L. Castro, Abraão A. Pinheiro, Karina R. da Silva, Lucilene R. de Souza, Francinaldo S. Braga, Carlos H. T. P. da Silva, Cleydson B. R. Santos, Lorane I. S. Hage-Melim

Journal of Pharmaceutical Research International, Page 152-175
DOI: 10.9734/BJPR/2015/18054

Aims: Alzheimer disease (AD) affects people aged 65 to 90 years and is the most prevalent neurodegenerative disease in the world. The deposition of β-amyloid peptide forming the amyloid plaques as well as neurofibrillary tangles deposition due to hyperphosphorylation of tau protein are the major cause of the disease in addition to the deficit of the neurotransmitter acetylcholine in the synaptic gap. Among the treatments for AD are acetylcholinesterase, beta-secretase and Glycogen Synthase Kinase-3β (GSK-3β) inhibitors. GSK-3β has been associated with all primary abnormalities of AD, because it interacts with the different components of the amyloid plaques production system and participates in the phosphorylation of tau protein. This regulates and stabilizes the microtubules in axons of the neurons of the Central Nervous System (CNS). The present study aimed to propose three novel candidates for inhibitors of GSK-3β.
Place and Duration of Study: Laboratory of Modeling and Computational Chemistry (LMCC) at Federal University of Amapá (UNIFAP), Macapá, Brazil, between November 2014 and March 2015.
Methodology: First, we used the crystal structure of GSK-3β enzyme deposited in the the Protein Data Bank (PDB) (PDB ID: 3Q3B – at 2.7 Å resolution). Then, we selected 50 inhibitors reported and available in the database BindingDB. Docking simulations were subsequently carried out using the AutoDock Vina 1.5.6 software. In sequence, a pharmacophore perception calculation was performed as well as and pharmacokinetic properties calculations. Finally, new proposals of GSK-3β inhibitors candidates were designed, considering in addition potential biological activity and synthetic accessibility as well as.
Results: In the study of physical and chemical parameters, most of the compounds violated no more than two parameters of the Lipinski’s Rule of five, indicating suitable oral absorption. Along of the docking simulations, 22 inhibitors showed strong interaction with the amino acid residues of the enzyme active site (hydrogen bond and hydrophobic interactions). Along of the pharmacophore perception calculation, 30 molecules lined up with four pharmacophore points: two aromatic rings and two hydrogen bond acceptor groups (in the case, pyrimidine group). Along the prediction of pharmacokinetics, the most of the potential GSK-3β inhibitors showed good permeability of Caco2 and MDCK cells, high absorption in the human intestine and weak binding to plasma proteins, but only two ones showed absorption in the blood brain barrier. The three proposals of GSK-3β inhibitor candidates indicate biological activity for GSK-3β, as well as having average synthetic accessibility.
Conclusion: This current study reveals three new promising compounds with in silico GSK-3β inhibitory activity. Therefore, further studies of quantitative structure-activity relationship as are necessary to investigate how the chemical structures of these molecules affect their biological potency and binding affinity for GSK-3β enzyme, and thus, selecting potential drug candidates for synthesis and biological testing.

Open Access Original Research Article

Antimicrobial Activity of Ethanolic Crude Extracts of Thespesia populnea Flowers

S. Solomon, N. Muruganantham, M. M. Senthamilselvi

Journal of Pharmaceutical Research International, Page 176-182
DOI: 10.9734/BJPR/2015/17307

Aim: To analyze the antimicrobial activity of ethanolic crude extract of Thespesia populnea Flowers.
Study Design: Antimicrobial activity of Thespesia populnea was carried out using disc diffusion method against crude extract.
Place and Duration of Study: PG & Research Department of Chemistry, Periyar E.V.R. College (Autonomous), Trichy, Tamilnadu, India. During the month of August and September 2014.
Methodology: Four bacterial strains such as S. typhi, E. coli, E. faecalis, B. cereus and two fungal strains such as C. lunata, and C. albicans were identified by using disc diffusion method. The anti bacterial activity of ethanolic extract is almost comparable with standard Chloramphenicol, which is used as an antibacterial agent. The anti fungal activity of ethanolic crude extract is almost comparable with standard Fluconazole, which is used as an antifungal agent.
Results: The disc diffusion method result showed the zone of inhibition for 10 mg/ml as 0 mm, 0 mm, 0 mm and 0 mm, for 20 mg/ml as 9 mm,0 mm , 0 mm and 7 mm, for 30 mg/ml showing 21 mm, 18 mm, 20 mm and 16 mm and for 40 mg/ml as 27 mm, 26 mm, 25 mm and 25 mm, against S. typhi, E. coli, E. faecalis and B. cereus respectively when compared with standard drug Chloramphenicol showing 22 mm, 19 mm, 23 mm and 25 mm zone of inhibition respectively. Then it is evident from the data presented in Table II that the sample possesses antifungal activity. The disc diffusion method result showed the zone of inhibition for 10 mg/ml as 0 mm and 0 mm, for 20 mg/ml as 9 mm and 0 mm, for 30 mg/ml as 19 mm and 18 mm and for 40 mg/ml as 23 mm and 26 mm against C. lunata, and C. albicans respectively when compared with standard drug Fluconazole showing 25 mm and 20 mm of inhibition respectively.
Conclusion: This study justifies the antimicrobial activity of ethanolic crude extract of Thespesia populnea Flowers. Further detailed analysis of this sample is required to identify the presence of bioactive compounds responsible for antibacterial and antifungal activities. Studies are highly needed for future drug development.

Open Access Original Research Article

Study and Evaluation of Medication Errors in Medicine and Orthopedic Wards of a Tertiary Care Hospital

Surendra Shrestha, K. V. Ramanath

Journal of Pharmaceutical Research International, Page 183-195
DOI: 10.9734/BJPR/2015/18736

Aims: The main aim of the present study was to detect and evaluate the incidence, types, factors and severity of medication errors in the medicine and orthopedic wards of a tertiary care hospital.
Study Design: This was a prospective and observational study.
Place and Duration of Study: Department of Medicine and Orthopedic wards of Sri Adichunchanagiri Hospital and Research Centre, B.G.Nagara-571448, Karnataka, India, between June 2014 to February 2015.
Methodology: The patients who satisfied inclusion and exclusion criteria were enrolled after obtaining their consent. The required data was collected in the Case Record Form and reviewed daily from the day of admission to discharge in the posted department. Different types of medication errors was identified, documented and the severity of medication error was identified by using NCC MERP guidelines.
Results: A total of 200 inpatient cases from orthopedic ward and medicine ward were collected, 100 cases from each ward. In orthopedic ward, 40% patients were of 20-39 years age and in medicine ward, 48% patients were of 60-79 years age. A total of 136 and 103 medication errors were observed in orthopedic and medicine ward, among them 65% and 62% were prescription errors, 25% and 18% were administration errors, 6% and 12% were transcription errors and 4% and 8% were dispensing errors. The cause of medication errors were 64.7% and 62.1% were due to physicians, 31.6% and 30.1% were due to nurses and 3.7% and 7.8% were due to pharmacists in orthopedic and medicine ward. Majority of medication errors 68.4% and 62.1% were belonged to category-B severity in orthopedic and medicine ward respectively.
Conclusion: Clinical pharmacist can play a major role in preventing medication errors by early detection. Since our system lacks a well-organize detection and reporting mechanism, Hence, as the first step we must implement a system where errors are routinely detected and reported.

Open Access Original Research Article

In vitro Equivalence Studies/Comparative Assessment of Generic Metronidazole Tablets Commercially Available in Lagos, Nigeria

Margaret O. Ilomuanya, Nabuogo A. Mbaneme, Omotunde O. Okubanjo, Kenneth Ofokansi

Journal of Pharmaceutical Research International, Page 196-205
DOI: 10.9734/BJPR/2015/18572

Purpose: For drug products to be interchangeably used by healthcare providers, formulation characteristics, which reflect variation within brands, batches and lots examined via dissolution profile analysis, must not show high statistical discrepancies. The objective of this study is to investigate the physicochemical and in vitro equivalence of thirteen brands of metronidazole tablets obtained from pharmacy retail outlets in Lagos, Nigeria.
Methods: Physicochemical characteristics comprising hardness, friability, drug content were evaluated in comparison with the innovator brand MZ-1. Dissolution data was analyzed using model dependent approach of dissolution efficiency and model independent approaches.
Results: The twelve generics brands were within compendial specified limits for hardness, friability, drug content and disintegration. Four of the brands MZ-3, 4, 10 and 13 were not pharmaceutically equivalent to the innovator brand MZ-1, Based on the results obtained from model-dependent method via dissolution efficiency where the release profile as a function of time was compared, the f1 and f2deciding the difference or similarity between dissolution profiles were used adequately utilized to decide pharmaceutical equivalence.
Conclusion: The extent to which these differences affected the amount of active constituent released over time in comparison with the innovator product was evident as only 8 of the brands MZ-2, 5, 6, 7, 8, 9, 11, 12 could be considered to be bioequivalent and thus interchangeably used with the innovator product.

Open Access Original Research Article

Anti-proliferative Effect of Isoflavones Isolated from Soybean and Soymilk Powder on Lymphoma (DG 75) and Leukemia (CEM) Cell Lines

C. Apprey, C. Larbie, F. K. N. Arthur, R. Appiah-Opong, R. A. Annan, I. Tuffour

Journal of Pharmaceutical Research International, Page 206-216
DOI: 10.9734/BJPR/2015/18363

Aim: Isoflavones in soybean have been linked to reduced risk of some cardiovascular diseases as well as some type of cancers. Extensive epidemiological, in-vitro and animal data suggests lower incidence of cardiovascular disease, hormone-dependent cancers of the breast and prostate, for consumers of soy and soy products. In this study, isoflavones were isolated from Soybean (SB) and soymilk powder (SMP) and the anti-proliferative effects of these isoflavones on Burkitt’s lymphoma (DG-75) and Leukemia (CEM) cell lines were investigated.
Place of Study: Department of Clinical Pathology, Noguchi Memorial Institute of Medical Research, University of Ghana, Accra, Ghana between June and December, 2014.
Methodology: Isoflavanoids were isolated and HPLC done to confirm the isolate. Isoflavanoids were isolated form SB and SMP and the anti-proliferative effect of isoflavanoid isolated from SB, SMP, pure genistein and daidzein on lymphoma and leukaemia cells were compared using tetrazolium-based colorimetric (MTT) assay.
Results: The inhibitory effect of genistein on leukemia (CEM) cell line was stronger (IC50 = 28.4 µM) than daidzein (IC50 = >100 µM). For the DG 75, genistein had a better effect (IC50 = 11.05 µM than daidzein (IC50> 100 µM). The IC50 for SMP were 193.92 µg/ml (DG-75) and 54.17 µg/ml (CEM). In terms of selectivity index (SI), genistein had the highest (>6.95) on CEM followed by genistein (>3.52) and then SB (>1.16).
Conclusion: SMP had a better anti-proliferative effect on both CEM and DG-75 compared with SB.

Open Access Original Research Article

In silico Identification of Novel Potential BACE-1 Inhibitors for Alzheimer’s Disease Treatment: Molecular Docking, Pharmacophore Modeling and Activity and Synthetic Accessibility Predictions

Abraão A. Pinhiero, Karina R. da Silva, Anna E. S. Silva, Francinaldo S. Braga, Carlos H. T. P. da Silva, Cleydson B. R. Santos, Lorane I. S. Hage-Melim

Journal of Pharmaceutical Research International, Page 217-229
DOI: 10.9734/BJPR/2015/18013

Aims: Alzheimer's Disease (AD) is a progressive neurodegenerative disease accompanied by loss of memory and cognition. With its causes still unknown, one of the main hypotheses related to its pathogenesis is the amyloidal, where the abnormal metabolism of amyloid precursor protein (APP), in this case cleaved by β-secretase enzyme (BACE-1), generates sAPPβ, subsequent action of β-secretase generates β-amyloid. This gives the β-secretase importance as a therapeutic target of AD, since their inhibition can control the onset and progression of the disease. This work intends to propose three new compounds with inhibitory activity for BACE-1 that may be potential drug candidates for AD treatment.
Place and Duration of Study: Laboratory of Modeling and Computational Chemistry (LMCC) at Federal University of Amapá (UNIFAP), Macapá, Brazil, between January 2014 and February 2015.
Methodology: First, we selected a group of inhibitors deposited in the BindingDB database as well as a crystallographic protein solved in the Protein Data Bank (PDB). Then we performed a prediction of ligand binding sites of BACE-1. To propose the binding mode of the inhibitor with the enzyme, molecular docking and molecular interactions analyses were performed. New proposals with potential inhibitory activity of BACE-1 in addition to a pharmacophore perception calculation as well as biological activity and synthetic accessibility predictions were made.
Results: A group of 40 inhibitors was selected from the database BindingDB, which were submitted to molecular docking simulation (for verification of the possible binding modes with the biological target), when analyzing the results of molecular docking, the hydrogen bond proved dominant over the others (approximately 74%). For pharmacophore perception calculation, the following characteristics were observed: a hydrophobic group, three aromatic groups, three donors and seven hydrogen bond acceptors. The target protein had its regions of the binding site predicted, and the most likely ligand binding site agree with the one already reported in the literature as the catalytic region of BACE-1. This allowed us to model three proposals that, in turn, had their predicted biological activities for BACE-1 as well as their synthetic accessibility.
Conclusion: Results showed that the proposals are promising BACE-1 inhibitors, with suitable drug-like properties, for future AD tretament.

Open Access Original Research Article

Antidiabetic Effects of Some Tropical Fruit Extracts in Fructose Induced Insulin Resistant Wistar Rats

Dorcas A. Wusu, Mutiu I. Kazeem, Oladipupo A. Lawal, Andy R. Opoku

Journal of Pharmaceutical Research International, Page 230-235
DOI: 10.9734/BJPR/2015/18718

Aim: Fruit extracts of Apple (Malus domestica), coconut (Cocos nucifera) and cucumber (Cucumis sativus) were tested for their antidiabetic potential in rats with fructose-induced insulin resistance for 28 days.
Study Design: In-vivo antidiabetic study using fructose-induced insulin resistant rats.
Place and Duration of Study: Department of Biochemistry, Lagos State University, Ojo, Lagos, Nigeria, between March and May 2014.
Methodology: Wistar rats were randomized into 5 groups comprising 5 animals each. Group A (control) was fed on standard rat chow and distilled water ad libitum while Groups B-E were fed standard rat chow and 10% w/v fructose. Groups C-E were also administered 500 mg/kg body weight of apple, coconut and cucumber extracts for 28 days. At the end of the experiment, all animals were sacrificed and the serum glucose, lipid profile and electrolytes were determined.
Results: The fructose-fed rats had significantly decreased weight and increased blood glucose concentration (P < 0.05), when compared to the control rats. The fructose-fed rats also witnessed significant increase (P < 0.05) in total cholesterol and low density lipoprotein cholesterol (LDLC) concentration as well as significant decrease (P < 0.05) in the high density lipoprotein (HDLC) and serum electrolytes concentration compared to control. Administration of the aqueous extracts of apple, coconut and cucumber to the fructose-fed rats significantly increase (P < 0.05) their body weights, HDLC and serum electrolytes’ concentration in the rats while significantly reducing (P < 0.05) blood glucose, total cholesterol and LDLC.
Conclusions: Aqueous extracts of apple, coconut and cucumber displayed antidiabetic effect, but apple exhibited the most potent effect as it ameliorates most of the derangements observed in insulin-resistant rats.