Displaying publications 1 - 20 of 54 in total

Abstract:
Sort:
  1. Ligand expansion in ligand-based virtual screening using relevance feedback
    Abdo A, Saeed F, Hamza H, Ahmed A, Salim N
    J Comput Aided Mol Des, 2012 Mar;26(3):279-87.
    PMID: 22249773 DOI: 10.1007/s10822-012-9543-4
    Query expansion is the process of reformulating an original query to improve retrieval performance in information retrieval systems. Relevance feedback is one of the most useful query modification techniques in information retrieval systems. In this paper, we introduce query expansion into ligand-based virtual screening (LBVS) using the relevance feedback technique. In this approach, a few high-ranking molecules of unknown activity are filtered from the outputs of a Bayesian inference network based on a single ligand molecule to form a set of ligand molecules. This set of ligand molecules is used to form a new ligand molecule. Simulated virtual screening experiments with the MDL Drug Data Report and maximum unbiased validation data sets show that the use of ligand expansion provides a very simple way of improving the LBVS, especially when the active molecules being sought have a high degree of structural heterogeneity. However, the effectiveness of the ligand expansion is slightly less when structurally-homogeneous sets of actives are being sought.
    Matched MeSH terms: Drug Evaluation, Preclinical/methods*
  2. New fragment weighting scheme for the Bayesian inference network in ligand-based virtual screening
    Abdo A, Salim N
    J Chem Inf Model, 2011 Jan 24;51(1):25-32.
    PMID: 21155550 DOI: 10.1021/ci100232h
    Many of the conventional similarity methods assume that molecular fragments that do not relate to biological activity carry the same weight as the important ones. One possible approach to this problem is to use the Bayesian inference network (BIN), which models molecules and reference structures as probabilistic inference networks. The relationships between molecules and reference structures in the Bayesian network are encoded using a set of conditional probability distributions, which can be estimated by the fragment weighting function, a function of the frequencies of the fragments in the molecule or the reference structure as well as throughout the collection. The weighting function combines one or more fragment weighting schemes. In this paper, we have investigated five different weighting functions and present a new fragment weighting scheme. Later on, these functions were modified to combine the new weighting scheme. Simulated virtual screening experiments with the MDL Drug Data Report (23) and maximum unbiased validation data sets show that the use of new weighting scheme can provide significantly more effective screening when compared with the use of current weighting schemes.
    Matched MeSH terms: Drug Evaluation, Preclinical/methods*
  3. Fulltext Knowledge-Based Methods To Train and Optimize Virtual Screening Ensembles
    Swift RV, Jusoh SA, Offutt TL, Li ES, Amaro RE
    J Chem Inf Model, 2016 05 23;56(5):830-42.
    PMID: 27097522 DOI: 10.1021/acs.jcim.5b00684
    Ensemble docking can be a successful virtual screening technique that addresses the innate conformational heterogeneity of macromolecular drug targets. Yet, lacking a method to identify a subset of conformational states that effectively segregates active and inactive small molecules, ensemble docking may result in the recommendation of a large number of false positives. Here, three knowledge-based methods that construct structural ensembles for virtual screening are presented. Each method selects ensembles by optimizing an objective function calculated using the receiver operating characteristic (ROC) curve: either the area under the ROC curve (AUC) or a ROC enrichment factor (EF). As the number of receptor conformations, N, becomes large, the methods differ in their asymptotic scaling. Given a set of small molecules with known activities and a collection of target conformations, the most resource intense method is guaranteed to find the optimal ensemble but scales as O(2(N)). A recursive approximation to the optimal solution scales as O(N(2)), and a more severe approximation leads to a faster method that scales linearly, O(N). The techniques are generally applicable to any system, and we demonstrate their effectiveness on the androgen nuclear hormone receptor (AR), cyclin-dependent kinase 2 (CDK2), and the peroxisome proliferator-activated receptor δ (PPAR-δ) drug targets. Conformations that consisted of a crystal structure and molecular dynamics simulation cluster centroids were used to form AR and CDK2 ensembles. Multiple available crystal structures were used to form PPAR-δ ensembles. For each target, we show that the three methods perform similarly to one another on both the training and test sets.
    Matched MeSH terms: Drug Evaluation, Preclinical/methods*
  4. Fulltext Ligand-based virtual screening using Bayesian networks
    Abdo A, Chen B, Mueller C, Salim N, Willett P
    J Chem Inf Model, 2010 Jun 28;50(6):1012-20.
    PMID: 20504032 DOI: 10.1021/ci100090p
    A Bayesian inference network (BIN) provides an interesting alternative to existing tools for similarity-based virtual screening. The BIN is particularly effective when the active molecules being sought have a high degree of structural homogeneity but has been found to perform less well with structurally heterogeneous sets of actives. In this paper, we introduce an alternative network model, called a Bayesian belief network (BBN), that seeks to overcome this limitation of the BIN approach. Simulated virtual screening experiments with the MDDR, WOMBAT and MUV data sets show that the BIN and BBN methods allow effective screening searches to be carried out. However, the results obtained are not obviously superior to those obtained using a much simpler approach that is based on the use of the Tanimoto coefficient and of the square roots of fragment occurrence frequencies.
    Matched MeSH terms: Drug Evaluation, Preclinical/methods*
  5. Fulltext Ligand-based virtual screening using Bayesian inference network and reweighted fragments
    Ahmed A, Abdo A, Salim N
    ScientificWorldJournal, 2012;2012:410914.
    PMID: 22623895 DOI: 10.1100/2012/410914
    Many of the similarity-based virtual screening approaches assume that molecular fragments that are not related to the biological activity carry the same weight as the important ones. This was the reason that led to the use of Bayesian networks as an alternative to existing tools for similarity-based virtual screening. In our recent work, the retrieval performance of the Bayesian inference network (BIN) was observed to improve significantly when molecular fragments were reweighted using the relevance feedback information. In this paper, a set of active reference structures were used to reweight the fragments in the reference structure. In this approach, higher weights were assigned to those fragments that occur more frequently in the set of active reference structures while others were penalized. Simulated virtual screening experiments with MDL Drug Data Report datasets showed that the proposed approach significantly improved the retrieval effectiveness of ligand-based virtual screening, especially when the active molecules being sought had a high degree of structural heterogeneity.
    Matched MeSH terms: Drug Evaluation, Preclinical/methods*
  6. Drug-like and non drug-like pattern classification based on simple topology descriptor using hybrid neural network
    Wan-Mamat WM, Isa NA, Wahab HA, Wan-Mamat WM
    Annu Int Conf IEEE Eng Med Biol Soc, 2009;2009:6424-7.
    PMID: 19964424 DOI: 10.1109/IEMBS.2009.5333747
    An intelligent prediction system has been developed to discriminate drug-like and non drug-like molecules pattern. The system is constructed by using the application of advanced version of standard multilayer perceptron (MLP) neural network called Hybrid Multilayer Perceptron (HMLP) neural network and trained using Modified Recursive Prediction Error (MRPE) training algorithm. In this work, a well understood and easy excess Rule of Five + Veber filter properties are selected as the topological descriptor. The main idea behind the selection of this simple descriptor is to assure that the system could be used widely, beneficial and more advantageous regardless at all user level within a drug discovery organization.
    Matched MeSH terms: Drug Evaluation, Preclinical/methods*
  7. Synthesis of new oxadiazole derivatives as α-glucosidase inhibitors
    Taha M, Ismail NH, Imran S, Rokei MQB, Saad SM, Khan KM
    Bioorg Med Chem, 2015 Aug 01;23(15):4155-4162.
    PMID: 26183542 DOI: 10.1016/j.bmc.2015.06.060
    Oxadiazole derivatives (6-28) having hydrazone linkage, were synthesized through condensation reaction between benzohydrazide 5 with various benzaldehydes. The oxadiazoles derivatives (6-28) were evaluated for their α-glucosidase inhibitory activity. The IC50 values for inhibition activity vary in the range between 2.64 ± 0.05 and 460.14 ± 3.25 μM. The IC50 values were being compared to the standard acarbose (IC50=856.45 ± 5.60 μM) and it was found that compounds 6-9, 12, 13, 16, 18, 20, 22-28 were found to be more active than acarbose, while other compounds showed no activity. Structure-activity relationship (SAR) studies suggest that oxadiazole benzohydrazones (6-28) inhibitory potential is dependent on substitution of the N-benzylidene part. Compound 18 (IC50=2.64 ± 0.05 μM), which has trihydroxy substitution at C-2', C-4', and C-5' on N-benzylidene moiety, recorded the highest inhibition activity that is three-hundred times more active than the standard drug, acarbose (IC50=856.45 ± 5.60 μM). Compound 23 (IC50=34.64 ± 0.35 μM) was found to be the most active among compounds having single hydroxyl substitution. Shifting hydroxyl from C-2' to C-4' (6) and C-3' (7) reduces inhibitory activity significantly. Compounds with chlorine substituent (compounds 16, 28, and 27) showed potent activities but lower as compared to hydroxyl analogs. Substituent like nitro or methyl groups at any position suppresses enzyme inhibition activity. This reveals the important presence of hydroxyl and halo groups to have enzyme inhibitory potential.
    Matched MeSH terms: Drug Evaluation, Preclinical/methods
  8. A bioactive cycloartane triterpene from Garcinia hombroniana
    Jamila N, Khan N, Khan I, Khan AA, Khan SN
    Nat Prod Res, 2016 Jun;30(12):1388-97.
    PMID: 26158779 DOI: 10.1080/14786419.2015.1060594
    The dichloromethane bark extract of Garcinia hombroniana yielded one new cycloartane triterpene; (22Z,24E)-3β-hydroxycycloart-14,22,24-trien-26-oic acid (1) together with five known compounds: garcihombronane G (2), garcihombronane J (3), 3β acetoxy-9α-hydroxy-17,14-friedolanostan-14,24-dien-26-oic acid (4), (22Z, 24E)-3β, 9α-dihydroxy-17,14-friedolanostan-14,22,24-trien-26-oic acid (5) and 3β, 23α-dihydroxy-17,14-friedolanostan-8,14,24-trien-26-oic acid (6). Their structures were established by the spectral techniques of NMR and ESI-MS. These compounds together with some previously isolated compounds; garcihombronane B (7), garcihombronane D (8) 2,3',4,5'-tetrahydroxy-6-methoxybenzophenone (9), volkensiflavone (10), 4''-O-methyll-volkensiflavone (11), volkensiflavone-7-O-glucopyranoside (12), volkensiflavone-7-O-rhamnopyranoside (13), Morelloflavone (14), 3''-O-methyl-morelloflavone (15) and morelloflavone-7-O-glucopyranoside (16) were evaluated for cholinesterase enzymes inhibitory activities using acetylcholinesterase and butyrylcholinesterase. In these activities, compounds 1-9 showed good dual inhibition on both the enzymes while compounds 10-16 did not reasonably contribute to both the cholinesterases inhibitory effects.
    Matched MeSH terms: Drug Evaluation, Preclinical/methods
  9. An evaluation of crude palm oil (CPO) and tocotrienol rich fraction (TRF) of palm oil as percutaneous permeation enhancers using full-thickness human skin
    Singh I, Nair RS, Gan S, Cheong V, Morris A
    Pharm Dev Technol, 2019 Apr;24(4):448-454.
    PMID: 30084268 DOI: 10.1080/10837450.2018.1509347
    The drawbacks associated with chemical skin permeation enhancers such as skin irritation and toxicity necessitated the research to focus on potential permeation enhancers with a perceived lower toxicity. Crude palm oil (CPO) is obtained by direct compression of the mesocarp of the fruit of the oil palm belonging to the genus Elaeis. In this research, CPO and tocotrienol-rich fraction (TRF) of palm oil were evaluated for the first time as skin permeation enhancers using full-thickness human skin. The in vitro permeation experiments were conducted using excised human skin mounted in static upright 'Franz-type' diffusion cells. The drugs selected to evaluate the enhancing effects of these palm oil derivatives were 5-fluorouracil, lidocaine and ibuprofen: compounds covering a wide range of Log p values. It was demonstrated that CPO and TRF were capable of enhancing the percutaneous permeation of drugs across full-thickness human skin in vitro. Both TRF and CPO were shown to significantly enhance the permeation of ibuprofen with flux values of 30.6 µg/cm2 h and 23.0 µg/cm2 h respectively, compared to the control with a flux of 16.2 µg/cm2 h. The outcome of this research opens further scope for investigation on the transdermal penetration enhancement activity of pure compounds derived from palm oil.
    Matched MeSH terms: Drug Evaluation, Preclinical/methods
  10. Aphrodisiac evaluation in non-copulator male rats after chronic administration of Eurycoma longifolia Jack
    Ang HH, Ngai TH
    Fundam Clin Pharmacol, 2001 Aug;15(4):265-8.
    PMID: 11564133 DOI: 10.1046/j.1472-8206.2001.00038.x
    The aphrodisiac effect of Eurycoma longifolia Jack (0.5 g/kg) was evaluated in noncopulator male rats using an electrical cage. Fractions of E. longifolia Jack decreased the hesitation time of noncopulator male rats, throughout the investigation period. Furthermore, it possessed a transient increase in the percentage of the male rats responding to the right choice, more than 50% of the male rats scored "right choice" after 3 weeks post-treatment and the effect became more prominent after 8 weeks post-treatment (only 40-50% of the control male rats responded to the right choice) using the electrical copulation cage. Hence, this study lends further support to the use of the plant by indigenous populations as a traditional medicine for its aphrodisiac property.
    Matched MeSH terms: Drug Evaluation, Preclinical/methods
  11. Design, synthesis, in vitro cytotoxicity evaluation and structure-activity relationship of goniothalamin analogs
    Mohideen M, Zulkepli S, Nik-Salleh NS, Zulkefeli M, Weber JF, Weber JF, et al.
    Arch Pharm Res, 2013 Jul;36(7):812-31.
    PMID: 23543632 DOI: 10.1007/s12272-013-0099-1
    A series of six/five member (E/Z)-Goniothalamin analogs were synthesized from commercially available (3,4-dihydro-2H-pyran-2-yl)methanol/5-(hydroxymethyl)dihydrofuran-2(3H)-one in three steps with good to moderate overall yields and their cytotoxicity against lymphoblastic leukemic T cell line (Jurkat E6.1) have been evaluated. Among the synthesized analogs, (Z)-Goniothalamin appeared to be the most active in cytotoxicity (IC50 = 12 μM). Structure-activity relationship study indicates that introducing substituent in phenyl ring or replacing phenyl ring by pyridine/naphthalene, or decreasing the ring size of lactones (from six to five member) do not increase the cytotoxicity.
    Matched MeSH terms: Drug Evaluation, Preclinical/methods
  12. In vitro and in vivo evaluation of self-microemulsifying drug delivery system of buparvaquone
    Venkatesh G, Majid MI, Mansor SM, Nair NK, Croft SL, Navaratnam V
    Drug Dev Ind Pharm, 2010 Jun;36(6):735-45.
    PMID: 20136493 DOI: 10.3109/03639040903460446
    The aim of this study was to prepare a lipid-based self-microemulsifying drug delivery system (SMEDDS) to increase the solubility and oral bioavailability of a poorly water-soluble compound, buparvaquone (BPQ).
    Matched MeSH terms: Drug Evaluation, Preclinical/methods
  13. Evaluation of superabsorbent linseed-polysaccharides as a novel stimuli-responsive oral sustained release drug delivery system
    Haseeb MT, Hussain MA, Bashir S, Ashraf MU, Ahmad N
    Drug Dev Ind Pharm, 2017 Mar;43(3):409-420.
    PMID: 27808567 DOI: 10.1080/03639045.2016.1257017
    CONTEXT: Advancement in technology has transformed the conventional dosage forms to intelligent drug delivery systems. Such systems are helpful for targeted and efficient drug delivery with minimum side effects. Drug release from these systems is governed and controlled by external stimuli (pH, enzymes, ions, glucose, etc.). Polymeric biomaterial having stimuli-responsive properties has opened a new area in drug delivery approach.

    OBJECTIVE: Potential of a polysaccharide (rhamnogalacturonan)-based hydrogel from Linseeds (Linum usitatissimum L.) was investigated as an intelligent drug delivery material.

    MATERIALS AND METHODS: Different concentrations of Linseed hydrogel (LSH) were used to prepare caffeine and diacerein tablets and further investigated for pH and salt solution-responsive swelling, pH-dependent drug release, and release kinetics. Morphology of tablets was observed using SEM.

    RESULTS: LSH tablets exhibited dynamic swelling-deswelling behavior with tendency to swell at pH 7.4 and in deionized water while deswell at pH 1.2, in normal saline and ethanol. Consequently, pH controlled release of the drugs was observed from tablets with lower release (<10%) at pH 1.2 and higher release at pH 6.8 and 7.4. SEM showed elongated channels in swollen then freeze-dried tablets.

    DISCUSSION: The drug release was greatly influenced by the amount of LSH in the tablets. Drug release from LSH tablets was governed by the non-Fickian diffusion.

    CONCLUSIONS: These finding indicates that LSH holds potential to be developed as sustained release material for tablet.

    Matched MeSH terms: Drug Evaluation, Preclinical/methods
  14. Fulltext Antinociceptive activities of a novel diarylpentanoid analogue, 2-benzoyl-6-(3-bromo-4-hydroxybenzylidene)cyclohexen-1-ol, and its possible mechanisms of action in mice
    Ong HM, Azmi AFA, Leong SW, Abas F, Perimal EK, Farouk AAO, et al.
    Sci Rep, 2021 12 16;11(1):24121.
    PMID: 34916536 DOI: 10.1038/s41598-021-02961-1
    A novel synthetic compound from the 2-benzoyl-6-benzylidenecyclohexanone analogue, namely 2-benzoyl-6-(3-bromo-4-hydroxybenzylidene)cyclohexen-1-ol (BBHC), showed pronounced nitric oxide inhibition in IFN-γ/LPS-induced RAW 264.7 cells. Based on this previous finding, our present study aimed to investigate the antinociceptive effects of BBHC via chemical and thermal stimuli in vivo. The investigation of the antinociceptive activity of BBHC (0.1, 0.3, 1.0 and 3.0 mg/kg, i.p.) was initiated with 3 preliminary screening tests, then BBHC was subjected to investigate its possible involvement with excitatory neurotransmitters and opioid receptors. The potential acute toxicity of BBHC administration was also studied. Administration of BBHC significantly inhibited acetic acid-induced abdominal constrictions, formalin-induced paw licking activity and developed notable increment in the latency time. BBHC's ability to suppress capsaicin- and glutamate-induced paw licking activities, as well as to antagonise the effect of naloxone, had indicated the possible involvement of its antinociception with TRPV1, glutamate and opioid receptors, respectively. The antinociceptive activities of BBHC was not related to any sedative action and no evidence of acute toxic effect was detected. The present study showed that BBHC possessed significant peripheral and central antinociceptive activities via chemical- and thermal-induced nociceptive murine models without any locomotor alteration and acute toxicity.
    Matched MeSH terms: Drug Evaluation, Preclinical/methods
  15. A screening method for cardiovascular active compounds in marine algae
    Agatonovic-Kustrin S, Kustrin E, Angove MJ, Morton DW
    J Chromatogr A, 2018 May 18;1550:57-62.
    PMID: 29615323 DOI: 10.1016/j.chroma.2018.03.054
    The interaction of bioactive compounds from ethanolic extracts of selected marine algae samples, separated on chromatographic plates, with nitric/nitrous acid was investigated. The nature of bioactive compounds in the marine algae extracts was characterised using UV absorption spectra before and after reaction with diluted nitric acid, and from the characteristic colour reaction after derivatization with anisaldehyde. It was found that diterpenes from Dictyota dichotoma, an edible brown algae, and sterols from green algae Caulerpa brachypus, bind nitric oxide and may act as a nitric oxide carrier. Although the carotenoid fucoxanthin, found in all brown marine algae also binds nitric oxide, the bonds between nitrogen and the fucoxanthin molecule are much stronger. Further studies are required to evaluate the effects of diterpenes from Dictyota dichotoma and sterols from green algae Caulerpa brachypus to see if they have beneficial cardiovascular effects. The method reported here should prove useful in screening large numbers of algae species for compounds with cardiovascular activity.
    Matched MeSH terms: Drug Evaluation, Preclinical/methods*
  16. Fulltext Evaluation of luciferase and GFP-expressing Nipah viruses for rapid quantitative antiviral screening
    Lo MK, Nichol ST, Spiropoulou CF
    Antiviral Res, 2014 Jun;106:53-60.
    PMID: 24680955 DOI: 10.1016/j.antiviral.2014.03.011
    Nipah virus (NiV) outbreaks have occurred in Malaysia, India, and Bangladesh, and the virus continues to cause annual outbreaks of fatal human encephalitis in Bangladesh due to spillover from its bat host reservoir. Due to its high pathogenicity, its potential use for bio/agro-terrorism, and to the current lack of approved therapeutics, NiV is designated as an overlap select agent requiring biosafety level-4 containment. Although the development of therapeutic monoclonal antibodies and soluble protein subunit vaccines have shown great promise, the paucity of effective antiviral drugs against NiV merits further exploration of compound libraries using rapid quantitative antiviral assays. As a proof-of-concept study, we evaluated the use of fluorescent and luminescent reporter NiVs for antiviral screening. We constructed and rescued NiVs expressing either Renilla luciferase or green fluorescent protein, and characterized their reporter signal kinetics in different cell types as well as in the presence of several inhibitors. The 50% effective concentrations (EC50s) derived for inhibitors against both reporter viruses are within range of EC50s derived from virus yield-based dose-response assays against wild-type NiV (within 1Log10), thus demonstrating that both reporter NiVs can serve as robust antiviral screening tools. Utilizing these live NiV-based reporter assays requires modest instrumentation, and circumvents the time and labor-intensive steps associated with cytopathic effect or viral antigen-based assays. These reporter NiVs will not only facilitate antiviral screening, but also the study of host cell components that influence the virus life cycle.
    Matched MeSH terms: Drug Evaluation, Preclinical/methods*
  17. Cytotoxic effects of commercial wheatgrass and fiber towards human acute promyelocytic leukemia cells (HL60)
    Alitheen NB, Oon CL, Keong YS, Chuan TK, Li HK, Yong HW
    Pak J Pharm Sci, 2011 Jul;24(3):243-50.
    PMID: 21715255
    Cytotoxicity, the possible selective activity upon HL60 as well as the anti-proliferation effect of local health supplement wheatgrass and mixture of fibers were investigated in vitro using various cancerous cell line and normal blood cell culture. The IC(50) of wheatgrass-treated HL60 (17.5 ± 1.1, 12.5 ± 0.3, and 16 ± 0.5 microgram/ml for 24, 48 and 72 h, respectively) and fibers-treated HL60 (86.0 ± 5.5, 35.0 ± 2.5, and 52.5 ± 4.5 microgram/ml for 24, 48 and 72 h, respectively) showed that both extracts possessed optimum effect after 48 hours of treatment. No significant cytotoxic effect was observed on other type of cells. For trypan blue dye exclusion method, wheatgrass reduced the number of viable cells by 13.5% (±1.5), 47.1% (±3.6), and 64.9% (±2.7) after 24, 48 and 72 h exposure, respectively. Mixture of fibers reduced the number of viable cells by 36.4% (±2.3), 57.1% (±3.1), and 89.0% (±3.4) after 24, 48 and 72 h exposure, respectively, indicated that necrosis is also an alternative to the apoptotic mechanism of cell death. Annexin-V/propidium iodide staining revealed that both extracts induced apoptosis where early apoptosis had been detected concurrently with the reduction of percentage of cell viability. Cell cycle analysis revealed that in HL60, the percentage of apoptosis increased with time (wheatgrass: 16.0% ± 2.4, 45.3% ± 3.4 and 39.6% ± 4.1; mixture of fibers: 14.6% ± 1.8, 45.4% ± 2.3 and 45.9% ± 1.2) after exposure for 24, 48 and 72 h, respectively at the concentration of 100 microgram/ml and showed optimum effect at 48 hours. Thus, these health products can be a potential alternative supplement for leukaemia patients.
    Matched MeSH terms: Drug Evaluation, Preclinical/methods
  18. Blood-brain barrier permeable anticholinesterase aurones: synthesis, structure-activity relationship, and drug-like properties
    Liew KF, Chan KL, Lee CY
    Eur J Med Chem, 2015 Apr 13;94:195-210.
    PMID: 25768702 DOI: 10.1016/j.ejmech.2015.02.055
    A series of novel aurones bearing amine and carbamate functionalities at various positions (rings A and/or B) of the scaffold was synthesized and evaluated for their acetylcholinesterase and butyrylcholinesterase inhibitory activities. Structure-activity relationship study disclosed several potent submicromolar acetylcholinesterase inhibitors (AChEIs) particularly aurones bearing piperidine and pyrrolidine moieties at ring A or ring B. Bulky groups particularly methoxyls, and carbamate to a lesser extent, at either rings were also prominently featured in these AChEI aurones as exemplified by the trimethoxyaurone 4-3. The active aurones exhibited a lower butyrylcholinesterase inhibition. A 3'-chloroaurone 6-3 originally designed to improve the metabolic stability of the scaffold was the most potent of the series. Molecular docking simulations showed these AChEI aurones to adopt favourable binding modes within the active site gorge of the Torpedo californica AChE (TcAChE) including an unusual chlorine-π interaction by the chlorine of 6-3 to establish additional bondings to hydrophobic residues of TcAChE. Evaluation of the potent aurones for their blood-brain barrier (BBB) permeability and metabolic stability using PAMPA-BBB assay and in vitro rat liver microsomes (RLM) identified 4-3 as an aurone with an optimal combination of high passive BBB permeability and moderate CYP450 metabolic stability. LC-MS identification of a mono-hydroxylated metabolite found in the RLM incubation of 4-3 provided an impetus for further improvement of the compound. Thus, 4-3, discovered within this present series is a promising, drug-like lead for the development of the aurones as potential multipotent agents for Alzheimer's disease.
    Matched MeSH terms: Drug Evaluation, Preclinical/methods
  19. Fulltext Life-span extension by pigmented rice bran in the model yeast Saccharomyces cerevisiae
    Sunthonkun P, Palajai R, Somboon P, Suan CL, Ungsurangsri M, Soontorngun N
    Sci Rep, 2019 12 02;9(1):18061.
    PMID: 31792269 DOI: 10.1038/s41598-019-54448-9
    Benefits of whole grains as dietary supplements and active ingredients in health products have been promoted. Despite being neglected as an agricultural byproduct of polished rice, pigmented rice bran has emerged as a promising source of natural anti-aging compounds. Indeed, the extract of red rice bran Hom Dang cultivar contained rich phenolic acids and flavonoids. It displayed high antioxidant activities in vitro and in vivo assays. Using yeast model, extract and bioactive compounds, quercetin and protocatechuic acid found in the rice bran pericarp, effectively reduced levels of intracellular reactive oxygen species (ROS), restored plasma membrane damages and prolonged life-span of pre-treated wild-yeast cells. Importantly, these molecules modulated life span-extension through a mechanism of ROS reduction that resembles to that operated under the highly conserved Tor1- and Sir2-dependent signaling pathways, with the human homologs TORC1 and SIRT1, respectively. The key longevity factors Sch9 and Rim15 kinases, Msn2/4 regulators and a novel transcription factor Asg1, the antioxidant enzymes superoxide dismutases and glutathione peroxidases played important role in mediating longevity. Yeast clearly provides an instrumental platform for rapid screening of compounds with anti-aging efficacies and advances knowledge in the molecular study of ageing.
    Matched MeSH terms: Drug Evaluation, Preclinical/methods
  20. Enhancing a search for traditional medicinal plants with anthelmintic action by using wild type and stress reporter Caenorhabditis elegans strains as screening tools
    Kumarasingha R, Palombo EA, Bhave M, Yeo TC, Lim DS, Tu CL, et al.
    Int J Parasitol, 2014 Apr;44(5):291-8.
    PMID: 24583111 DOI: 10.1016/j.ijpara.2014.01.008
    Traditional healers in Sarawak, Malaysia, use plants such as Picria fel-terrae, Linariantha bicolor and Lansium domesticum to treat gastrointestinal infections. This study aimed to test whether their nematocidal activities could be confirmed in vitro using highly standardised Caenorhabditis elegans models. We applied eight different ethanol solubilised plant extracts and two commercial anthelmintic drugs to larval and adult stages of C. elegans in vitro. Seven C. elegans strains were evaluated, one wild type and six strains with GFP-tagged stress response pathways to help characterise and compare the pathways affected by plant extracts. Our in vitro screen confirmed that both of the commercial anthelmintic drugs and five of the eight traditionally used plant extracts had significant nematocidal activity against both larval and adult C. elegans. The most effective extracts were from P. fel-terrae. The plant extracts triggered different stress response pathways from the commercial anthelmintic drugs. This study showed that using traditional knowledge of plant medicinal properties in combination with a C. elegans in vitro screen provided a rapid and economical test with a high hit rate compared with the random screening of plants for nematocidal activities. The use of transgenic C. elegans strains may allow this approach to be refined further to investigate the mode of action of active extracts.
    Matched MeSH terms: Drug Evaluation, Preclinical/methods*
Related Terms
Filters
Contact Us

Please provide feedback to Administrator (afdal@afpm.org.my)

External Links