Displaying publications 81 - 100 of 355 in total

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  1. Fulltext First comprehensive in silico analysis of the functional and structural consequences of SNPs in human GalNAc-T1 gene
    Mohamoud HS, Hussain MR, El-Harouni AA, Shaik NA, Qasmi ZU, Merican AF, et al.
    Comput Math Methods Med, 2014;2014:904052.
    PMID: 24723968 DOI: 10.1155/2014/904052
    GalNAc-T1, a key candidate of GalNac-transferases genes family that is involved in mucin-type O-linked glycosylation pathway, is expressed in most biological tissues and cell types. Despite the reported association of GalNAc-T1 gene mutations with human disease susceptibility, the comprehensive computational analysis of coding, noncoding and regulatory SNPs, and their functional impacts on protein level, still remains unknown. Therefore, sequence- and structure-based computational tools were employed to screen the entire listed coding SNPs of GalNAc-T1 gene in order to identify and characterize them. Our concordant in silico analysis by SIFT, PolyPhen-2, PANTHER-cSNP, and SNPeffect tools, identified the potential nsSNPs (S143P, G258V, and Y414D variants) from 18 nsSNPs of GalNAc-T1. Additionally, 2 regulatory SNPs (rs72964406 and #x26; rs34304568) were also identified in GalNAc-T1 by using FastSNP tool. Using multiple computational approaches, we have systematically classified the functional mutations in regulatory and coding regions that can modify expression and function of GalNAc-T1 enzyme. These genetic variants can further assist in better understanding the wide range of disease susceptibility associated with the mucin-based cell signalling and pathogenic binding, and may help to develop novel therapeutic elements for associated diseases.
    Matched MeSH terms: Models, Molecular
  2. Role of surface-exposed charged basic amino acids (Lys, Arg) and guanidination in insulin on the interaction and stability of insulin-insulin receptor complex
    Lee VS, Sukumaran SD, Tan PK, Kuppusamy UR, Arumugam B
    Comput Biol Chem, 2021 Jun;92:107501.
    PMID: 33989998 DOI: 10.1016/j.compbiolchem.2021.107501
    Naturally occurring proteins are emerging as novel therapeutics in the protein-based biopharmaceutical industry for the treatment of diabetes and obesity. However, proteins are not suitable for oral delivery due to short half-life, reduced physical and chemical stability and low permeability across the membrane. Chemical modification has been identified as a formulation strategy to enhance the stability and bioavailability of protein drugs. The present study aims to study the effect of charge-specific modification of basic amino acids (Lys, Arg) and guanidination on the interaction of insulin with its receptor using molecular modelling. Our investigation revealed that the guanidination of insulin (Lys-NHC = NHNH2) enhanced and exerted stronger binding of the protein to its receptor through electrostatic interaction than native insulin (Lys-NH3+). Point mutations of Lys and Arg (R22, K29; R22K, K29; R22, K29R; R22K, K29R) were attempted and the effects on the interaction and stability between insulin/modified insulins and insulin receptor were also analyzed in this study. The findings from the study are expected to provide a better understanding of the possible mechanism of action of the modified protein at a molecular level before advancing to real experiments.
    Matched MeSH terms: Models, Molecular
  3. In silico analysis and characterization of medicinal mushroom cystathionine beta-synthase as an angiotensin converting enzyme (ACE) inhibitory protein
    Goh NY, Mohamad Razif MF, Yap YH, Ng CL, Fung SY
    Comput Biol Chem, 2022 Feb;96:107620.
    PMID: 34971900 DOI: 10.1016/j.compbiolchem.2021.107620
    Angiotensin-converting enzyme (ACE) regulates blood pressure and has been implicated in several conditions including lung injury, fibrosis and Alzheimer's disease. Medicinal mushroom Ganordema lucidum (Reishi) cystathionine beta-synthase (GlCBS) was previously reported to possess ACE inhibitory activities. However, the inhibitory mechanism of CBS protein remains unreported. Therefore, this study integrates in silico sequencing, structural and functional based-analysis, protein modelling, molecular docking and binding affinity calculation to elucidate the inhibitory mechanism of GlCBS and Lignosus rhinocerus (Tiger milk mushroom) CBS protein (LrCBS) towards ACE. In silico analysis indicates that CBSs from both mushrooms share high similarities in terms of physical properties, structural properties and domain distribution. Protein-protein docking analysis revealed that both GlCBS and LrCBS potentially modulate the C-terminal domain of ACE (C-ACE) activity via regulation of chloride activation and/or prevention of substrate entry. GICBS and LrCBS were also shown to interact with ACE at the same region that presumably inhibits the function of ACE.
    Matched MeSH terms: Models, Molecular
  4. Fulltext Identification of novel human USP2 inhibitor and its putative role in treatment of COVID-19 by inhibiting SARS-CoV-2 papain-like (PLpro) protease
    Mirza MU, Ahmad S, Abdullah I, Froeyen M
    Comput Biol Chem, 2020 Dec;89:107376.
    PMID: 32979815 DOI: 10.1016/j.compbiolchem.2020.107376
    Human ubiquitin carboxyl-terminal hydrolase-2 (USP2) inhibitors, such as thiopurine analogs, have been reported to inhibit SARS-CoV papain-like proteases (PLpro). The PLpro have significant functional implications in the innate immune response during SARS-CoV-2 infection and considered an important antiviral target. Both proteases share strikingly similar USP fold with right-handed thumb-palm-fingers structural scaffold and conserved catalytic triad Cys-His-Asp/Asn. In this urgency situation of COVID-19 outbreak, there is a lack of in-vitro facilities readily available to test SARS-CoV-2 inhibitors in whole-cell assays. Therefore, we adopted an alternate route to identify potential USP2 inhibitor through integrated in-silico efforts. After an extensive virtual screening protocol, the best compounds were selected and tested. The compound Z93 showed significant IC50 value against Jurkat (9.67 μM) and MOTL-4 cells (11.8 μM). The binding mode of Z93 was extensively analyzed through molecular docking, followed by MD simulations, and molecular interactions were compared with SARS-CoV-2. The relative binding poses of Z93 fitted well in the binding site of both proteases and showed consensus π-π stacking and H-bond interactions with histidine and aspartate/asparagine residues of the catalytic triad. These results led us to speculate that compound Z93 might be the first potential chemical lead against SARS-CoV-2 PLpro, which warrants in-vitro evaluations.
    Matched MeSH terms: Models, Molecular
  5. Application of solid-phase extraction for trace elements in environmental and biological samples: a review
    Wan Ibrahim WA, Abd Ali LI, Sulaiman A, Sanagi MM, Aboul-Enein HY
    Crit Rev Anal Chem, 2014;44(3):233-54.
    PMID: 25391563 DOI: 10.1080/10408347.2013.855607
    The progress of novel sorbents and their function in preconcentration techniques for determination of trace elements is a topic of great importance. This review discusses numerous analytical approaches including the preparation and practice of unique modification of solid-phase materials. The performance and main features of ion-imprinting polymers, carbon nanotubes, biosorbents, and nanoparticles are described, covering the period 2007-2012. The perspective and future developments in the use of these materials are illustrated.
    Matched MeSH terms: Models, Molecular
  6. Domperidone nanocrystals with boosted oral bioavailability: fabrication, evaluation and molecular insight into the polymer-domperidone nanocrystal interaction
    Ndlovu ST, Ullah N, Khan S, Ramharack P, Soliman M, de Matas M, et al.
    Drug Deliv Transl Res, 2019 Feb;9(1):284-297.
    PMID: 30387048 DOI: 10.1007/s13346-018-00596-w
    The aim of this study was to employ experimental and molecular modelling approaches to use molecular level interactions to rationalise the selection of suitable polymers for use in the production of stable domperidone (DOMP) nanocrystals with enhanced bioavailability. A low-energy antisolvent precipitation method was used for the preparation and screening of polymers for stable nanocrystals of DOMP. Ethyl cellulose was found to be very efficient in producing stable DOMP nanocrystals with particle size of 130 ± 3 nm. Moreover, the combination of hydroxypropyl methylcellulose and polyvinyl alcohol was also shown to be better in producing DOMP nanocrystals with smaller particle size (200 ± 3.5 nm). DOMP nanosuspension stored at 2-8 °C and at room temperature (25 °C) exhibited better stability compared to the samples stored at 40 °C. Crystallinity of the unprocessed and processed DOMP was monitored by differential scanning calorimetry and powder X-ray diffraction. DOMP nanocrystals gave enhanced dissolution rate compared to the unprocessed drug substance. DOMP nanocrystals at a dose of 10 mg/kg in rats showed enhanced bioavailability compared to the raw drug substance and marketed formulation. A significant increase in plasma concentration of 2.6 μg/mL with a significant decrease in time (1 h) to reach maximum plasma concentration was observed for DOMP nanocrystals compared to the raw DOMP. Molecular modelling studies provided underpinning knowledge at the molecular level of the DOMP-polymer nanocrystal interactions and substantiated the experimental studies. This included an understanding of the impact of polymers on the size of nanocrystals and their associated stability characteristics.
    Matched MeSH terms: Models, Molecular
  7. Fulltext Synthesis, structural characterization, and anticancer activity of a monobenzyltin compound against MCF-7 breast cancer cells
    Fani S, Kamalidehghan B, Lo KM, Hashim NM, Chow KM, Ahmadipour F
    Drug Des Devel Ther, 2015;9:6191-201.
    PMID: 26648695 DOI: 10.2147/DDDT.S87064
    A new monoorganotin Schiff base compound, [N-(3,5-dichloro-2-oxidobenzylidene)-4-chlorobenzyhydrazidato](o-methylbenzyl)aquatin(IV) chloride, (compound C1), was synthesized, and its structural features were investigated by spectroscopic techniques and single-crystal X-ray diffractometry. Compound C1 was exposed to several human cancer cell lines, including breast adenocarcinoma cell lines MCF-7 and MDA-MB-231, ovarian adenocarcinoma cell lines Skov3 and Caov3, and prostate cancer cell line PC3, in order to examine its cytotoxic effect for different forms of cancer. Human hepatic cell line WRL-68 was used as a normal cell line. We concentrated on the MCF-7 cell line to detect possible underlying mechanism involvement of compound C1. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed the strongest cytotoxicity of compound C1 against MCF-7 cells, with a half maximal inhibitory concentration (IC50) value of 2.5±0.50 μg/mL after 48 hours treatment. The IC50 value was >30 μg/mL in WRL-68 cells. Induced antiproliferative activity of compound C1 for MCF-7 cells was further confirmed by lactate dehydrogenase, reactive oxygen species, acridine orange/propidium iodide staining, and DNA fragmentation assays. A significant increase of lactate dehydrogenase release in treated cells was observed via fluorescence analysis. Luminescent analysis showed significant growth in intracellular reactive oxygen species production after treatment. Morphological changes of necrosis and early and late apoptosis stages were observed in treated cells after staining with acridine orange/propidium iodide. DNA fragmentation was observed as a characteristic of apoptosis in treated cells. Results of the present study obviously reveal potential cytotoxic effects of compound C1 against human breast cancer MCF-7 cells.
    Matched MeSH terms: Models, Molecular
  8. Fulltext Engineering of Naproxen Loaded Polymer Hybrid Enteric Microspheres for Modified Release Tablets: Development, Characterization, in silico Modelling and in vivo Evaluation
    Hameed HA, Khan S, Shahid M, Ullah R, Bari A, Ali SS, et al.
    Drug Des Devel Ther, 2020;14:27-41.
    PMID: 32021089 DOI: 10.2147/DDDT.S232111
    BACKGROUND: Naproxen (NP) is a non-steroidal anti-inflammatory drug with poor aqueous solubility and low oral bioavailability, which may lead to therapeutic failure. NP causes crucial GIT irritation, bleeding, and peptic and duodenal ulcers.

    PURPOSE OF THE STUDY: This study aimed to engineer and characterize polymer hybrid enteric microspheres using an integrated (experimental and molecular modelling) approach with further development to solid dosage form with modified drug release kinetics and improved bioavailability.

    MATERIALS AND METHODS: NP loaded polymer hybrid enteric microspheres (PHE-Ms) were fabricated by using a modified solvent evaporation technique coupled with molecular modelling (MM) approach. The PHE-Ms were characterized by particle size, distribution, morphology, crystallinity, EE, drug-polymer compatibility, and DSC. The optimized NP loaded PHE-Ms were further subjected to downstream procedures including tablet dosage form development, stability studies and comparative in vitro-in vivo evaluation.

    RESULTS: The hydrophobic polymer EUD-L100 and hydrophilic polymer HPMC-E5 delayed and modified drug release at intestinal pH while imparting retardation of NP release at gastric pH to diminish the gastric side effects. The crystallinity of the NP loaded PHE-Ms was established through DSC and P (XRD). The particle size for the developed formulations of PEH-Ms (M1-M5) was in the range from 29.06 ±7.3-74.31 ± 17.7 μm with Span index values of 0.491-0.69, respectively. The produced NP hybrid microspheres demonstrated retarded drug release at pH 1.2 and improved dissolution at pH 6.8. The in vitro drug release patterns were fitted to various release kinetic models and the best-followed model was the Higuchi model with a release exponent "n" value > 0.5. Stability studies at different storage conditions confirmed stability of the NP loaded PHE-Ms based tablets (P<0.05). The molecular modelling (MM) study resulted in adequate binding energy of co-polymer complex SLS-Eudragit-HPMC-Naproxen (-3.9 kcal/mol). In contrast to the NP (unprocessed) and marketed formulations, a significant increase in the Cmax of PHE-MT1 (44.41±4.43) was observed.

    CONCLUSION: The current study concludes that developing NP loaded PHE-Ms based tablets could effectively reduce GIT consequences with restored therapeutic effects. The modified release pattern could improve the dissolution rate and enhancement of oral bioavailability. The MM study strengthens the polymer-drug relationship in microspheres.

    Matched MeSH terms: Models, Molecular
  9. Photocatalytic degradation of resorcinol, an endocrine disrupter, by TiO2 and ZnO suspensions
    Lam SM, Sin JC, Abdullah AZ, Mohamed AR
    Environ Technol, 2013 May-Jun;34(9-12):1097-106.
    PMID: 24191441
    In the work presented here, photocatalytic systems using TiO2 and ZnO suspensions were utilized to evaluate the degradation of resorcinol (ReOH). The effects of catalyst concentration and solution pH were investigated and optimized using multivariate analysis based on response surface methodology. The results indicated that ZnO showed greater degradation and mineralization activities compared to TiO2 under optimized conditions. Using certain radical scavengers, a positive hole, together with the participation of hydroxyl radicals, were the oxidative species responsible for ReOH degradation on TiO2 whereas, the ZnO photocatalysis occurred principally via hydroxyl radicals. Some hitherto unreported pathway intermediates of ReOH degradation were identified using gas chromatography-mass spectrometry. A tentative reaction mechanism for the formation of these intermediates was proposed. Moreover, the figure-of-merit electrical energy per order was employed to estimate the electrical energy consumption.
    Matched MeSH terms: Models, Molecular
  10. NCI in vitro and in silico anticancer screen, cell cycle pertubation and apoptosis-inducing potential of new acylated, benzylidene and isopropylidene derivatives of andrographolide
    Wong CC, Sagineedu SR, Sumon SH, Sidik SM, Phillips R, Lajis NH, et al.
    Environ Toxicol Pharmacol, 2014 Sep;38(2):489-501.
    PMID: 25168151 DOI: 10.1016/j.etap.2014.07.016
    Andrographolide (AGP) is the main bioactive constituent isolated from the traditional medicinal, Andrographis paniculata which contributes towards its various biological activities, including anticancer property. In this study, a series of new AGP derivatives were semi-synthesised and screened against the NCI in vitro 60 cell lines. From the screening results, we had identified SRS07 as the most potent AGP derivative, against breast and colon cancer cell lines. Subsequently, SRS07 was tested for its capability to induce cell cycle arrest and apoptosis in MCF-7 and HCT116 cancer cells. SRS07 effectively induced G1 cell cycle arrest in both cell lines and ultimately apoptosis by inducing DNA fragmentation in HCT116 cells. The apoptotic cell death induced by SRS07 was confirmed via FITC Annexin-V double staining. Western blot analysis of SRS07-treated HCT116 cells revealed that the compound induced apoptosis be activating caspase 8 which in turn cleaved Bid to t-Bid to initiate cell death cascade. Prediction of the possible mode of action of SRS07 by utilising NCI COMPARE analysis failed to reveal a distinct mechanism category. Hence, it is speculated that SRS07 possesses novel mechanism of action. In conclusion, SRS07 demonstrated superior in vitro anticancer profiles and emerged as a potential lead anticancer candidate.
    Matched MeSH terms: Models, Molecular
  11. Functional characterisation and product specificity of Endo-β-1,3-glucanase from alkalophilic bacterium, Bacillus lehensis G1
    Jaafar NR, Khoiri NM, Ismail NF, Mahmood NAN, Abdul Murad AM, Abu Bakar FD, et al.
    Enzyme Microb Technol, 2020 Oct;140:109625.
    PMID: 32912685 DOI: 10.1016/j.enzmictec.2020.109625
    Endo-β-1,3-glucanase from alkalophilic bacterium, Bacillus lehensis G1 (Blg32) composed of 284 amino acids with a predicted molecular mass of 31.6 kDa is expressed in Escherichia coli and purified to homogeneity. Herein, Blg32 characteristics, substrates and product specificity as well as structural traits that might be involved in the production of sugar molecules are analysed. This enzyme functions optimally at the temperature of 70 °C, pH value of 8.0 with its catalytic activity strongly enhanced by Mn2+. Remarkably, the purified enzyme is highly stable in high temperature and alkaline conditions. It exhibits the highest activity on laminarin (376.73 U/mg) followed by curdlan and yeast β-glucan. Blg32 activity increased by 62% towards soluble substrate (laminarin) compared to insoluble substrate (curdlan). Hydrolytic products of laminarin were oligosaccharides with degree of polymerisation (DP) of 1 to 5 with the main product being laminaritriose (DP3). This suggests that the active site of Blg32 could recognise up to five glucose units. High concentration of Blg32 mainly produces glucose whilst low concentration of Blg32 yields oligosaccharides with different DP (predominantly DP3). A theoretical structural model of Blg32 was constructed and structural analysis revealed that Trp156 is involved in multiple hydrophobic stacking interactions. The amino acid was predicted to participate in substrate recognition and binding. It was also exhibited that catalytic groove of Blg32 has a narrow angle, thus limiting the substrate binding reaction. All these properties and knowledge of the subsites are suggested to be related to the possible mode of action of how Blg32 produces glucooligosaccharides.
    Matched MeSH terms: Models, Molecular
  12. Crystal structure of a compact α-amylase from Geobacillus thermoleovorans
    Mok SC, Teh AH, Saito JA, Najimudin N, Alam M
    Enzyme Microb Technol, 2013 Jun 10;53(1):46-54.
    PMID: 23683704 DOI: 10.1016/j.enzmictec.2013.03.009
    A truncated form of an α-amylase, GTA, from thermophilic Geobacillus thermoleovorans CCB_US3_UF5 was biochemically and structurally characterized. The recombinant GTA, which lacked both the N- and C-terminal transmembrane regions, functioned optimally at 70°C and pH 6.0. While enzyme activity was not enhanced by the addition of CaCl2, GTA's thermostability was significantly improved in the presence of CaCl2. The structure, in complex with an acarbose-derived pseudo-hexasaccharide, consists of the typical three domains and binds one Ca(2+) ion. This Ca(2+) ion was strongly bound and not chelated by EDTA. A predicted second Ca(2+)-binding site, however, was disordered. With limited subsites, two novel substrate-binding residues, Y147 and Y182, may help increase substrate affinity. No distinct starch-binding domain is present, although two regions rich in aromatic residues have been observed. GTA, with a smaller domain B and several shorter loops compared to other α-amylases, has one of the most compact α-amylase folds that may contribute greatly to its tight Ca(2+) binding and thermostability.
    Matched MeSH terms: Models, Molecular
  13. PASS-assisted design, synthesis and antioxidant evaluation of new butylated hydroxytoluene derivatives
    Ariffin A, Rahman NA, Yehye WA, Alhadi AA, Kadir FA
    Eur J Med Chem, 2014 Nov 24;87:564-77.
    PMID: 25299680 DOI: 10.1016/j.ejmech.2014.10.001
    New multipotent antioxidants (MPAOs), namely 1,3,4-thiadiazoles and 1,2,4-triazoles bearing the well-known free radical scavenger butylated hydroxytoluene (BHT), were designed and synthesized using an acid-(base-) catalyzed intramolecular dehydrative cyclization reaction of the corresponding 1-acylthiosemicarbazides. The structure-activity relationship (SAR) of the designed antioxidants was performed along with the prediction of activity spectra for substances (PASS) training set. Experimental studies based on antioxidant activity using DPPH and lipid peroxidation assays verified the predictions obtained by the PASS-assisted design strategy. Compounds 4a-b, 5a-b and 6a-b showed an inhibition of stable DPPH free radicals at a 10(-4) M more than the well-known standard antioxidant BHT. Compounds with p-methoxy substituents (4b, 5b and 6b) were more active than o-methoxy substituents (4a, 5a and 6a). With an IC50 of 2.85 ± 1.09 μM, compound 6b exhibited the most promising in vitro inhibition of lipid peroxidation, inhibiting Fe(2+)-induced lipid peroxidation of essential oils derived from the egg yolk-based lipid-rich medium by 86.4%. The parameters for the drug-likeness of these BHT derivatives were also evaluated according to Lipinski's 'rule-of-five'. All of the BHT derivatives were found to violate one of Lipinski's parameters (Log P ≥ 5) even though they have been found to be soluble in protic solvents. The predictive TPSA and %ABS data allow for the conclusion that these compounds could have a good capacity for penetrating cell membranes. Therefore, these novel MPAOs containing lipophilic and hydrophilic groups can be proposed as potential antioxidants for tackling oxidative stress and lipid peroxidation processes.
    Matched MeSH terms: Models, Molecular
  14. Discovery of azetidine based ene-amides as potent bacterial enoyl ACP reductase (FabI) inhibitors
    Takhi M, Sreenivas K, Reddy CK, Munikumar M, Praveena K, Sudheer P, et al.
    Eur J Med Chem, 2014 Sep 12;84:382-94.
    PMID: 25036796 DOI: 10.1016/j.ejmech.2014.07.036
    A novel and potent series of ene-amides featuring azetidines has been developed as FabI inhibitors active against drug resistant Gram-positive pathogens particularly staphylococcal organisms. Most of the compounds from the series possessed excellent biochemical inhibition of Staphylococcus aureus FabI enzyme and whole cell activity against clinically relevant MRSA, MSSA and MRSE organisms which are responsible for significant morbidity and mortality in community as well as hospital settings. The binding mode of one of the leads, AEA16, in Escherichia coli FabI enzyme was determined unambiguously using X-ray crystallography. The lead compounds displayed good metabolic stability in mice liver microsomes and pharmacokinetic profile in mice. The in vivo efficacy of lead AEA16 has been demonstrated in a lethal murine systemic infection model.
    Matched MeSH terms: Models, Molecular
  15. Synthesis, crystal structures and characterization of late first row transition metal complexes derived from benzothiazole core: anti-tuberculosis activity and special emphasis on DNA binding and cleavage property
    Netalkar PP, Netalkar SP, Budagumpi S, Revankar VK
    Eur J Med Chem, 2014 May 22;79:47-56.
    PMID: 24721314 DOI: 10.1016/j.ejmech.2014.03.083
    Air and moisture stable coordination compounds of late first row transition metals, viz. Co(II), Ni(II), Cu(II) and Zn(II), with a newly designed ligand, 2-(2-benzo[d]thiazol-2-yl)hydrazono)propan-1-ol (LH), were prepared and successfully characterized using various spectro-analytical techniques. The molecular structures of the ligand and nickel complex were unambiguously determined by single-crystal X-ray diffraction method. The [Ni(LH)2]Cl2.3H2O complex is stabilized by intermolecular CH⋯π stacking interactions between the methyl hydrogen and the C18 atom of the phenyl ring (C11-H11B⋯C18) forming 1D zig-zag chain structure. Both, the ligand and its copper complex, were electrochemically active in the working potential range, showing quasi-reversible redox system. The interactions of all the compounds with calf thymus DNA have been comprehensively investigated using electronic absorption spectroscopy, viscosity, electrochemistry and thermal denaturation studies. The cleavage reaction on pBR322 DNA has been monitored by agarose gel electrophoresis. The results showed that the ligand can bind to CT-DNA through partial intercalation, whereas the complexes bind electrostatically. Further, [Ni(LH)2]Cl2.3H2O and [CuLCl(H2O)2] complexes in the series have high binding and cleavage affinity towards pBR322 DNA. Additionally, all the compounds were screened for anti-tuberculosis activity. All the complexes revealed an MIC value of 0.8 μg/mL, which is almost 8 times active than standard used (Streptomycin, 6.25 μg/mL).
    Matched MeSH terms: Models, Molecular
  16. Discovery of mixed type thymidine phosphorylase inhibitors endowed with antiangiogenic properties: synthesis, pharmacological evaluation and molecular docking study of 2-thioxo-pyrazolo[1,5-a][1,3,5]triazin-4-ones. Part II
    Bera H, Ojha Pk, Tan BJ, Sun L, Dolzhenko AV, Chui WK, et al.
    Eur J Med Chem, 2014 May 6;78:294-303.
    PMID: 24686016 DOI: 10.1016/j.ejmech.2014.03.063
    In our drug discovery program, a series of 2-thioxo-pyrazolo[1,5-a][1,3,5]triazin-4-ones were designed, synthesized and evaluated for their TP inhibitory potential. All the synthesized analogues conferred a varying degree of TP inhibitory activity, comparable or better than positive control, 7-deazaxanthine (7-DX, 2) (IC50 value = 42.63 μM). A systematic approach to the lead optimization identified compounds 3c and 4a as the most promising TP inhibitors, exhibiting mixed mode of enzyme inhibition. Moreover, selected compounds demonstrated the ability to attenuate the expression of the angiogenic markers (viz. MMP-9 and VEGF) in MDA-MB-231 cells at sublethal concentrations. In addition, molecular docking studies revealed the plausible binding orientation of these inhibitors towards TP, which was in accordance with the experimental results. Taken as a whole, these compounds would constitute a new direction for the design of novel TP inhibitors with promising antiangiogenic properties.
    Matched MeSH terms: Models, Molecular
  17. Copper complexes with phosphonium containing hydrazone ligand: topoisomerase inhibition and cytotoxicity study
    Chew ST, Lo KM, Lee SK, Heng MP, Teoh WY, Sim KS, et al.
    Eur J Med Chem, 2014 Apr 9;76:397-407.
    PMID: 24602785 DOI: 10.1016/j.ejmech.2014.02.049
    Four new copper(II) complexes containing phosphonium substituted hydrazone (L) with the formulations [CuL]Cl(3), [Cu(phen)L]Cl(4), [Cu(bpy)L]Cl(5), [Cu(dbpy)L]Cl(6), (where L = doubly deprotonated hydrazone; phen = 1,10'-phenanthroline; bpy = 2,2'-bipyridine; dbpy = 5,5'-dimethyl-2,2'-bipyridine) have been synthesized. The compounds were characterized by elemental analysis, spectroscopic methods and in the case of crystalline products by X-ray crystallography. The cytotoxicity and topoisomerase I (topo I) inhibition activities of these compounds were studied. It is noteworthy that the addition of N,N-ligands to the copper(II) complex lead to the enhancement in the cytotoxicity of the compounds, especially against human prostate adenocarcinoma cell line (PC-3). Complex 4 exhibits the highest activity against PC-3 with the IC₅₀ value of 3.2 μΜ. The complexes can also inhibit topo I through the binding to DNA and the enzyme.
    Matched MeSH terms: Models, Molecular
  18. Click chemistry approach: regioselective one-pot synthesis of some new 8-trifluoromethylquinoline based 1,2,3-triazoles as potent antimicrobial agents
    Garudachari B, Isloor AM, Satyanarayana MN, Fun HK, Hegde G
    Eur J Med Chem, 2014 Mar 3;74:324-32.
    PMID: 24486415 DOI: 10.1016/j.ejmech.2014.01.008
    Three series of 8-trifluoromethylquinoline based 1,2,3-triazoles derivatives (5a-c, 6a-d and 7a-c) were synthesized by multi-step reactions by click chemistry approach. Synthesized compounds were characterized by spectral studies and X-ray analysis. The final compounds were screened for their in-vitro antimicrobial activity by well plate method (zone of inhibition). Compounds 5c, 6b, 8b, 11 and 12 were found to be active against tested microbial strains. The results are summarized in Tables 5 and 6.
    Matched MeSH terms: Models, Molecular
  19. Phosphanegold(I) dithiocarbamates, R3PAu[SC(=S)N((i)Pr)CH2CH2OH] for R = Ph, Cy and Et: role of phosphane-bound R substituents upon in vitro cytotoxicity against MCF-7R breast cancer cells and cell death pathways
    Jamaludin NS, Goh ZJ, Cheah YK, Ang KP, Sim JH, Khoo CH, et al.
    Eur J Med Chem, 2013 Sep;67:127-41.
    PMID: 23856069 DOI: 10.1016/j.ejmech.2013.06.038
    The synthesis and characterisation of R3PAu[S2CN((i)Pr)CH2CH2OH], for R = Ph (1), Cy (2) and Et (3)4, is reported. Compounds 1-3 are cytotoxic against the doxorubicin-resistant breast cancer cell line, MCF-7R, with 1 exhibiting greater potency and cytotoxicity than either of doxorubicin and cisplatin. Based on human apoptosis PCR-array analysis, caspase activities, DNA fragmentation, cell apoptotic assays, intracellular reactive oxygen species (ROS) measurements and human topoisomerase I inhibition, induction of apoptosis by 1, and necrosis by 2 and 3, are demonstrated, by both extrinsic and intrinsic pathways. Compound 1 activates the p53 gene, 2 activates only the p73 gene, whereas 3 activates both the p53 and p73 genes. Compounds 1 and 3 activate NF-κB, and each inhibits topoisomerase I.
    Matched MeSH terms: Models, Molecular
  20. An expedient, ionic liquid mediated multi-component synthesis of novel piperidone grafted cholinesterase enzymes inhibitors and their molecular modeling study
    Basiri A, Murugaiyah V, Osman H, Kumar RS, Kia Y, Awang KB, et al.
    Eur J Med Chem, 2013 Sep;67:221-9.
    PMID: 23871902 DOI: 10.1016/j.ejmech.2013.06.054
    Series of hitherto unreported piperidone grafted pyridopyrimidines synthesized through ionic liquid mediated multi-component reaction. These compounds were evaluated for their inhibitory activities against AChE and BChE enzymes. All the compounds displayed considerable potency against AChE with IC50 values ranging from 0.92 to 9.11 μM, therein compounds 6a, 6h and 6i displayed superior enzyme inhibitory activities compared to standard drug with IC50 values of 0.92, 1.29 and 2.07 μM. Remarkably, all the compounds displayed higher BChE inhibitory activity compared to galantamine with IC50 values of 1.89-8.13 μM. Molecular modeling, performed for the most active compounds using three dimensional crystal structures of TcAChE and hBChE, disclosed binding template of these inhibitors into the active site of their respective enzymes.
    Matched MeSH terms: Models, Molecular
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