Displaying publications 141 - 160 of 262 in total

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  1. Dinuclear Gold(I) Pyrrolidinedithiocarbamato Complex: Cytotoxic and Antimigratory Activities on Cancer Cells and the Use of Metal-Organic Framework
    Sun RW, Zhang M, Li D, Zhang ZF, Cai H, Li M, et al.
    Chemistry, 2015 Dec 14;21(51):18534-8.
    PMID: 26459298 DOI: 10.1002/chem.201503656
    A dinuclear gold(I) pyrrolidinedithiocarbamato complex (1) with a bidentate carbene ligand has been constructed and shows potent in vitro cytotoxic activities towards cisplatin-resistant ovarian cancer cells A2780cis. Its rigid scaffold enables a zinc(II)-based metal-organic framework (Zn-MOF) to be used as a carrier in facilitating the uptake and release of 1 in solutions. Instead of using a conventional dialysis approach for the drug-release testing, in this study, a set of transwell assay-based experiments have been designed and employed to examine the cytotoxic and antimigratory activities of 1@Zn-MOF towards A2780cis.
    Matched MeSH terms: Ligands
  2. Synthesis, spectral studies and biological evaluation of 2-aminonicotinic acid metal complexes
    Nawaz M, Abbasi MW, Hisaindee S, Zaki MJ, Abbas HF, Mengting H, et al.
    Spectrochim Acta A Mol Biomol Spectrosc, 2016 May 15;161:39-43.
    PMID: 26945123 DOI: 10.1016/j.saa.2016.02.022
    We synthesized 2-aminonicotinic acid (2-ANA) complexes with metals such as Co(II), Fe(III), Ni(II), Mn(II), Zn(II), Ag(I),Cr(III), Cd(II) and Cu(II) in aqueous media. The complexes were characterized and elucidated using FT-IR, UV-Vis, a fluorescence spectrophotometer and thermo gravimetric analysis (TGA). TGA data showed that the stoichiometry of complexes was 1:2 metal/ligand except for Ag(I) and Mn(II) where the ratio was 1:1. The metal complexes showed varied antibacterial, fungicidal and nematicidal activities. The silver and zinc complexes showed highest activity against Bacillus subtilis and Bacillus licheniformis respectively. Fusarium oxysporum was highly susceptible to nickel and copper complexes whereas Macrophomina phaseolina was completely inert to the complexes. The silver and cadmium complexes were effective against the root-knot nematode Meloidogyne javanica.
    Matched MeSH terms: Ligands
  3. Stabilization of Human Serum Albumin against Urea Denaturation by Diazepam and Ketoprofen
    Manoharan P, Wong YH, Tayyab S
    Protein Pept Lett, 2015;22(7):611-7.
    PMID: 25961707
    Stabilizing effect of diazepam and ketoprofen, Sudlow's site II markers on human serum albumin (HSA) against urea denaturation was studied using fluorescence spectroscopy. The two-step, three-state urea transition of HSA was transformed into a single-step, two-state transition with the abolishment of the intermediate state along with a shift of the transition curve towards higher urea concentrations in the presence of diazepam or ketoprofen. Interestingly, a greater shift in the transition curve of HSA was observed in the presence of ketoprofen compared to diazepam. A comparison of the intrinsic fluorescence and three-dimensional fluorescence spectra of HSA and partially-denatured HSAs, obtained in the absence and the presence of diazepam or ketoprofen suggested significant retention of native-like conformation in the partially-denatured states of HSA in the presence of Sudlow's site II markers. Taken together, all these results suggested stabilization of HSA in the presence of diazepam or ketoprofen, being greater in the presence of ketoprofen.
    Matched MeSH terms: Ligands
  4. Nickel and zinc complexes of testosterone N4-substituted thiosemicarbazone: Selective cytotoxicity towards human colorectal carcinoma cell line HCT 116 and their cell death mechanisms
    Heng MP, Sim KS, Tan KW
    J Inorg Biochem, 2020 07;208:111097.
    PMID: 32438269 DOI: 10.1016/j.jinorgbio.2020.111097
    Two new Schiff base ligands (TE and TF) were prepared from conjugation of testosterone with 4-(4-ethylphenyl)-3-thiosemicarbazide and 4-(4-fluorophenyl)-3-thiosemicarbazide, respectively. Their nickel (NE and NF) and zinc (ZE and ZF) complexes were reported. X-ray crystallography revealed a distorted square planar geometry was adopted by NE. The compounds demonstrated excellent selectivity towards the colorectal carcinoma cell line HCT 116 despite their weak preferences towards the prostate cancer cell lines (PC-3 and LNCaP). Against HCT 116, all these compounds were able to arrest cell cycle at G0/G1 phase and induce apoptosis via mitochondria-dependent (TE, NE, and TF) and extrinsic apoptotic pathway (ZE, NF, and ZF). Moreover, only ZE was able to act as topoisomease I poison and halt its enzymatic reactions although all compounds presented excellent affinity towards DNA.
    Matched MeSH terms: Ligands
  5. Fulltext N-glycosylation and expression in human tissues of the orphan GPR61 receptor
    Kozielewicz P, Alomar H, Yusof S, Grafton G, Cooper AJ, Curnow SJ, et al.
    FEBS Open Bio, 2017 12;7(12):1982-1993.
    PMID: 29226084 DOI: 10.1002/2211-5463.12339
    A number of members of the G protein-coupled receptor class of cell surface receptors are 'orphans' with no known endogenous ligand. One of these orphan receptors is GPR61; there are little data about its expression in human cells and tissues. In this study, we investigated the post-translational modification of GPR61 by N-glycosylation at an identified consensus N-glycosylation site (N12) and the impact of this modification upon the subcellular expression of the protein. The N-glycosylation inhibitor tunicamycin reduced the apparent molecular weight of immunoreactivity associated with myc-tagged GPR61 by 1-2 kDa, which was comparable to the evident molecular weight of the myc-tagged N12S GPR61 mutant with disrupted consensus N-glycosylation site. Analysis of GPR61 expression demonstrated that tunicamycin treatment reduced considerably heterologous expression of GPR61 in the cell membrane despite the N12S GPR61 mutant being readily expressed at the cell surface. These results demonstrate that GPR61 is subject to N-glycosylation but suggest this is not a prerequisite for cell surface expression, although N-glycosylation of other proteins may be important for cell membrane expression of GPR61. Expression of GPR61 protein was demonstrated at the cellular level in human hippocampus and human peripheral blood mononuclear cells. In the latter, there was a significantly higher expression of GPR61 in the Th17 cell subset in comparison with resting CD4+ cells, which may point toward a potential role for the GPR61 receptor in autoimmune diseases. This is the first report that GPR61 protein is subject to post-translational modification and is expressed in immune cell subsets and the hippocampus. These findings will help guide studies to investigate the function of GPR61.
    Matched MeSH terms: Ligands
  6. Fulltext Expression of fibroblast growth factor receptor 4 (FGFR-4) in nasopharyngeal carcinoma (NPC) cell lines and its potential as therapeutic target
    Hooi Yeen Yap, Jack Bee Chook, Sin Yeang Teow
    Malaysian Journal of Medicine and Health Sciences, 2019;15(108):49-49.
    MyJurnal
    ntroduction: Nasopharyngeal carcinoma (NPC) is a prevalent cancer among human population in Southern China, Hong Kong and Southeast Asia. In Malaysia, NPC is the fourth most common cancer in both sexes, predominantly in the Chinese. Epstein-Barr virus (EBV) infection is known to be highly associated with NPC. Fibroblast growth factor receptor-4 (FGFR4) is part of the family of tyrosine kinase receptors that regulate cell survival, differentiation and pro-liferation. The binding of FGFR4 ligands such as fibroblasts growth factors (FGFs) has been shown to activate various oncogenic signalling pathway including MAPK, Ras and PI3K-Akt pathways. In the past, FGFR4 has been shown to promote tumorigenesis and tumour progression in various cancers such as liver, colon, breast and pancreatic and gastric cancers. However, its role in NPC establishment and pathogenesis is under-explored. This study aimed to evaluate the FGFR4 expression in NPC using various cell lines and its potential as a therapeutic target for NPC treat-ment by gene silencing. Methods: The basal FGFR4 level of NPC (EBV-positive: C666-1 and EBV-negative: HONE1 and HK1) and nasopharyngeal epithelial (NPE) normal (NP69 and NP460) cell lines was determined by western blot analysis and RT-qPCR. FGFR4 level at different time points (0, 24, 48, and 72 hours) in HONE1 and C666-1 cell lines were determined by western blot analysis. Luminescence-based assay was performed to determine the cell prolifer-ation of NPC cells in correlation with the FGFR4 expression. NPC cells were then treated with the optimised FGFR4 siRNA or FGFR inhibitor, BLU-9931 and the silencing/ inhibition of FGFR4 expression was confirmed by western blot analysis. The effect of FGFR4 inhibition on the cell proliferation and aggressiveness of NPC cells was then investigat-ed through wound healing assay and invasion marker analysis. Results: Out of the five tested cell lines, HONE1 and C666-1 highly expressed FGFR4, NP69 showed very low expression while HK1 and NP460 did not express FGFR4. In the time-point study, the FGFR4 level of HONE1 and C666-1 peaked at 24-48 hours which is the exponential phase of cells. Following that, the FGFR4 level decreased corresponding to the decreased cell growth rate due to the nutrient deprivation. siRNA experiments showed that 6.25nM of four siRNAs (5, 6, 9 and 10) could effectively target and silence the FGFR4 expression of HONE1, but not in C666-1 even up to 250nM was tested. When BLU-9931 was used, only modest inhibition was observed in both cells at 3uM. Compared to the untreated control, FGFR4-inhibited HONE1 exhibited decreased cell proliferation rate. Cell migration and invasion capabilities of HONE1 were also significantly reduced following the FGFR4 silencing, suggesting the potential of utilising FGFR4 as the therapeutic target. Conclusion: FGFR4 is highly expressed in C666-1 (EBV-positive) and HONE1 (initially EBV-positive, but lost EBV genome in subsequent in vitro passage) NPC cells, but not in EBV-negative HK1 NPC cell and normal NPE cells. FGFR4 gene silencing effectively inhibited the cell proliferation, migration and invasive potentials of NPC cell line. These findings highlight the therapeutic value of targeting FGFR4 for NPC treatment. Further investigations are war-ranted to reveal the molecular mechanism and the possible role of EBV in regulating FGFR4 pathway.
    Matched MeSH terms: Ligands
  7. Fulltext The Values of Receptor Activator Nuclear Kappa-B Ligand Expression in Stage III Giant Cell Tumor of the Bone
    Ghani SA, Wan Ismail WF, Md Salleh MS, Yahaya S, Syahrul Fitri ZM
    Indian J Orthop, 2018 2 9;52(1):31-34.
    PMID: 29416167 DOI: 10.4103/ortho.IJOrtho_153_17
    Background: Giant cell tumor (GCT) of bone is a benign locally aggressive primary bone tumor which is risky for local recurrences and pulmonary metastasis. Till date, there are still many uncertainties in predicting the aggressiveness of GCT. We aim to investigate whether receptor activator nuclear kappa-B ligand (RANKL) expression may determine the prognosis of the lesion.

    Materials and Methods: We examined RANKL expression in 39 patients (21 males, 18 females) by immunohistochemistry. Four patients (10%) were presented with tumor recurrence, eight patients (20%) were complicated with lung metastasis, and two patients (5%) were presented with both recurrence and lung metastasis. Positive RANKL expression was assessed according to a scoring system evaluating the percentage of the immunostained epithelial area and the staining intensity. The cumulative score was calculated to determine the final score value. Data were analyzed using PASW version 18.0 and independent t-test between nonrecurrence/recurrence groups, and nonlung metastasis/lung metastasis groups. Significance was set at P < 0.05.

    Results: Thirty-two patients (82%) scored 3 in RANKL-staining percentage from whole stromal cell population (>75%), 6 patients scored 2, and 1 patient scored 1. Nine patients (23%) scored 3 in RANKL-staining intensity (most intense), 19 patients (48%) scored 2, and 11 patients (29%) scored 1. Twenty six patients (67%) had strong RANKL expression (total score of 5-6), 12 patients (31%) showed moderate score (3-4) whereas only 1 patient (2%) showed weak RANKL expression. Together, the mean value of RANKL-staining percentage was 2.79, intensity 1.95 and the total score 4.77. The mean RANKL-staining percentage between recurrence and nonrecurrence groups was statistically significant (P = 0.009). There was no significant difference in the mean staining intensity and total score between nonrecurrence and recurrence groups, and staining percentage staining intensity and a total cumulative score of RANKL expression between lung metastasis and nonlung metastasis groups.

    Conclusion: RANKL expression is generally high in Stage III GCT and is a reliable prognostic marker in predicting the risk of local recurrence however not in lung metastasis.

    Matched MeSH terms: Ligands
  8. Neuropsychiatric implications of transient receptor potential vanilloid (TRPV) channels in the reward system
    Singh R, Bansal Y, Parhar I, Kuhad A, Soga T
    Neurochem Int, 2019 12;131:104545.
    PMID: 31494132 DOI: 10.1016/j.neuint.2019.104545
    Neuropsychiatric disorders (NPDs) exert a devastating impact on an individual's personal and social well-being, encompassing various conditions and brain anomalies that influence affect, cognition, and behavior. Because the pathophysiology of NPDs is multifactorial, the precise mechanisms underlying the development of such disorders remain unclear, representing a unique challenge in current neuropsychopharmacotherapy. Transient receptor potential vanilloid (TRPV) type channels are a family of ligand-gated ion channels that mainly include sensory receptors that respond to thermal, mechanical and chemical stimuli. TRPV channels are abundantly present in dopaminergic neurons, thus playing a pivotal role in the modulation of the reward system and in pathophysiology of diseases such as stress, anxiety, depression, schizophrenia, neurodegenerative disorders and substance abuse/addiction. Recent evidence has highlighted TRPV channels as potential targets for understanding modulation of the reward system and various forms of addiction (opioids, cocaine, amphetamines, alcohol, nicotine, cannabis). In this review, we discuss the distribution, physiological roles, ligands and therapeutic importance of TRPV channels with regard to NPDs and addiction biology.
    Matched MeSH terms: Ligands
  9. Synthesis of new indazole based dual inhibitors of α-glucosidase and α-amylase enzymes, their in vitro, in silico and kinetics studies
    Rafique R, Khan KM, Arshia, Kanwal, Chigurupati S, Wadood A, et al.
    Bioorg Chem, 2020 01;94:103195.
    PMID: 31451297 DOI: 10.1016/j.bioorg.2019.103195
    The current study describes the discovery of novel inhibitors of α-glucosidase and α-amylase enzymes. For that purpose, new hybrid analogs of N-hydrazinecarbothioamide substituted indazoles 4-18 were synthesized and fully characterized by EI-MS, FAB-MS, HRFAB-MS, 1H-, and 13C NMR spectroscopic techniques. Stereochemistry of the imine double bond was established by NOESY measurements. All derivatives 4-18 with their intermediates 1-3, were evaluated for in vitro α-glucosidase and α-amylase enzyme inhibition. It is worth mentioning that all synthetic compounds showed good inhibition potential in the range of 1.54 ± 0.02-4.89 ± 0.02 µM for α-glucosidase and for α-amylase 1.42 ± 0.04-4.5 ± 0.18 µM in comparison with the standard acarbose (IC50 value of 1.36 ± 0.01 µM). In silico studies were carried out to rationalize the mode of binding interaction of ligands with the active site of enzymes. Moreover, enzyme inhibitory kinetic characterization was also performed to understand the mechanism of enzyme inhibition.
    Matched MeSH terms: Ligands
  10. Synthesis, characterization and anti-cancer properties of water-soluble bis(PYE) pro-ligands and derived palladium(ii) complexes
    Zafar MN, Masood S, Chaudhry GE, Muhammad TST, Dalebrook AF, Nazar MF, et al.
    Dalton Trans, 2019 Aug 08.
    PMID: 31393494 DOI: 10.1039/c9dt01923e
    The two cationic palladium(ii) complexes, [Pd(Len)2][OTf]2 (4) and [Pd(Lphen)2][OTf]2 (5), were synthesized by treatment of bis(benzonitrile)dichloropalladium(ii) with [H2Len][OTf]2 (2) or [H2Lphen][OTf]2 (3), respectively, in the presence of a weak base. The pro-ligands 2 and 3 were synthesized by melt reactions between N-methyl-4-chloropyridinium triflate (1) and the amines ethylenediamine or phenylenediamine, respectively. The water-soluble compounds 2-5 were fully characterized, including by single-crystal X-ray crystal structure determinations for 2-4. UV-Vis and fluorescence spectroscopy were used to study the binding interactions of 2-5 with CT-DNA. The spectroscopic data suggested the presence of intercalative and groove binding modes and this was supported by molecular docking studies. The in vitro cytotoxicity studies (IC50 values) showed that the human breast cancer cell lines MCF-7 and T47D were more sensitive towards 3, 4 and 5 than cisplatin. The cytotoxicity of the new compounds decreased in the order 5 > 4 > 3 > 2. Furthermore, the annexin V-FITC staining method strongly suggested the presence of phosphatidylserine (PS) on the outer membrane of the treated cells, which is a hallmark of apoptosis.
    Matched MeSH terms: Ligands
  11. Exploring ligand-protein interaction: A laboratory exercise on herbicide binding to plasma transport protein
    Roslan AA, Tayyab S
    Biochem Mol Biol Educ, 2019 03;47(2):156-160.
    PMID: 30629781 DOI: 10.1002/bmb.21207
    A laboratory exercise on the interaction between the herbicide pendimethalin (PM) and goat serum albumin (GSA), a carrier protein present in mammalian blood circulation, is described. Fluorescence spectroscopy was used to study the binding reaction between PM and GSA. Titration of a constant amount of the protein (GSA) with increasing ligand (PM) concentrations produced a consecutive decrease in the protein's fluorescence. Treatment of the fluorescence quenching data according to the Stern-Volmer equation yielded the values of the Stern-Volmer constant (Ksv ) and bimolecular quenching rate constant (kq ), whereas values of the binding constant (Ka ) and number of binding sites (n) were obtained from the double logarithmic plot. This experiment provides an exciting opportunity for undergraduate students to independently perform ligand binding studies with a protein, in addition to providing the means for the determination of their binding parameters. © 2019 International Union of Biochemistry and Molecular Biology, 47(2): 156-160, 2019.
    Matched MeSH terms: Ligands
  12. Dihydroquinazolin-4(1H)-one derivatives as novel and potential leads for diabetic management
    Babatunde O, Hameed S, Salar U, Chigurupati S, Wadood A, Rehman AU, et al.
    Mol Divers, 2021 Mar 01.
    PMID: 33650031 DOI: 10.1007/s11030-021-10196-5
    A variety of dihydroquinazolin-4(1H)-one derivatives (1-37) were synthesized via "one-pot" three-component reaction scheme by treating aniline and different aromatic aldehydes with isatoic anhydride in the presence of acetic acid. Chemical structures of compounds were deduced by different spectroscopic techniques including EI-MS, HREI-MS, 1H-, and 13C-NMR. Compounds were subjected to α-amylase and α-glucosidase inhibitory activities. A number of derivatives exhibited significant to moderate inhibition potential against α-amylase (IC50 = 23.33 ± 0.02-88.65 ± 0.23 μM) and α-glucosidase (IC50 = 25.01 ± 0.12-89.99 ± 0.09 μM) enzymes, respectively. Results were compared with the standard acarbose (IC50 = 17.08 ± 0.07 μM for α-amylase and IC50 = 17.67 ± 0.09 μM for α-glucosidase). Structure-activity relationship (SAR) was rationalized by analyzing the substituents effects on inhibitory potential. Kinetic studies were implemented to find the mode of inhibition by compounds which revealed competitive inhibition for α-amylase and non-competitive inhibition for α-glucosidase. However, in silico study identified several important binding interactions of ligands (synthetic analogues) with the active site of both enzymes.
    Matched MeSH terms: Ligands
  13. The identification of active compounds in Ganoderma lucidum var. antler extract inhibiting dengue virus serine protease and its computational studies
    Lim WZ, Cheng PG, Abdulrahman AY, Teoh TC
    J Biomol Struct Dyn, 2020 Sep;38(14):4273-4288.
    PMID: 31595837 DOI: 10.1080/07391102.2019.1678523
    The number of global dengue incidences is alarmingly high in recent years. The global distribution of four dengue serotypes has also added economic burden in the dengue-endemic countries. To discover the potent dengue virus inhibitors in the antler form of Ganoderma lucidum (Lingzhi or Reishi), the water extraction of normal G. lucidum and its antler form were conducted and the chemical compounds were identified by LC-MS. Six distinct chemical compounds identified in high abundance were hesperetin, thymidine, lucidenic acid, 11-aminoundecanoic acid, 5-carboxyvanillic acid and ganocin B. The water extracts of G. lucidum in its antler form inhibited the DENV2 NS2B-NS3 protease activity at 84.6 ± 0.7%, higher than the normal G. lucidum. Then, molecular docking was performed on the homology model built from an in-house sequence. Docking simulation results showed that hesperetin and ganocin B were the best leads to bind at the catalytic triad of DENV2 NS2B-NS3pro via hydrogen bonding, van der Waals and pi-pi interactions. Extensive overlapping of HOMO-LUMO orbitals at the ringed regions of hesperetin helped to facilitate the entry of ligand to the catalytic triad cleft. LC-MS, molecular docking and density functional theory analyses confirmed that hesperetin was the strongest inhibitor against NS2B-NS3 protease. Communicated by Ramaswamy H. Sarma.
    Matched MeSH terms: Ligands
  14. Fulltext Highly Active Cellulose-Supported Poly(hydroxamic acid)-Cu(II) Complex for Ullmann Etherification
    Jian Fui C, Xin Ting T, Sarjadi MS, Amin Z, Sarkar SM, Musta B, et al.
    ACS Omega, 2021 Mar 16;6(10):6766-6779.
    PMID: 33748590 DOI: 10.1021/acsomega.0c05840
    Highly active natural pandanus-extracted cellulose-supported poly(hydroxamic acid)-Cu(II) complex 4 was synthesized. The surface of pandanus cellulose was modified through graft copolymerization using purified methyl acrylate as a monomer. Then, copolymer methyl acrylate was converted into a bidentate chelating ligand poly(hydroxamic acid) via a Loosen rearrangement in the presence of an aqueous solution of hydroxylamine. Finally, copper species were incorporated into poly(hydroxamic acid) via the adsorption process. Cu(II) complex 4 was fully characterized by Fourier transform infrared (FTIR), field emission scanning electron microscopy (FE-SEM), energy-dispersive X-ray (EDX), transmission electron microscopy (TEM), inductively coupled plasma optical emission spectrometry (ICP-OES), thermogravimetric analysis (TGA), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS) analyses. The cellulose-supported Cu(II) complex 4 was successfully applied (0.005 mol %) to the Ullmann etherification of aryl, benzyl halides, and phenacyl bromide with a number of aromatic phenols to provide the corresponding ethers with excellent yield [benzyl halide (70-99%); aryl halide (20-90%)]. Cu(II) complex 4 showed high stability and was easily recovered from the reaction mixture. It could be reused up to seven times without loss of its original catalytic activity. Therefore, Cu(II) complex 4 can be commercially utilized for the preparation of various ethers, and this synthetic technique could be a part in the synthesis of natural products and medicinal compounds.
    Matched MeSH terms: Ligands
  15. Fulltext Heterocyclic Substitutions Greatly Improve Affinity and Stability of Folic Acid towards FRα. an In Silico Insight
    Al-Thiabat MG, Saqallah FG, Gazzali AM, Mohtar N, Yap BK, Choong YS, et al.
    Molecules, 2021 Feb 18;26(4).
    PMID: 33670773 DOI: 10.3390/molecules26041079
    Folate receptor alpha (FRα) is known as a biological marker for many cancers due to its overexpression in cancerous epithelial tissue. The folic acid (FA) binding affinity to the FRα active site provides a basis for designing more specific targets for FRα. Heterocyclic rings have been shown to interact with many receptors and are important to the metabolism and biological processes within the body. Nineteen FA analogs with substitution with various heterocyclic rings were designed to have higher affinity toward FRα. Molecular docking was used to study the binding affinity of designed analogs compared to FA, methotrexate (MTX), and pemetrexed (PTX). Out of 19 FA analogs, analogs with a tetrazole ring (FOL03) and benzothiophene ring (FOL08) showed the most negative binding energy and were able to interact with ASP81 and SER174 through hydrogen bonds and hydrophobic interactions with amino acids of the active site. Hence, 100 ns molecular dynamics (MD) simulations were carried out for FOL03, FOL08 compared to FA, MTX, and PTX. The root mean square deviation (RMSD) and root mean square fluctuation (RMSF) of FOL03 and FOL08 showed an apparent convergence similar to that of FA, and both of them entered the binding pocket (active site) from the pteridine part, while the glutamic part was stuck at the FRα pocket entrance during the MD simulations. Molecular mechanics Poisson-Boltzmann surface accessible (MM-PBSA) and H-bond analysis revealed that FOL03 and FOL08 created more negative free binding and electrostatic energy compared to FA and PTX, and both formed stronger H-bond interactions with ASP81 than FA with excellent H-bond profiles that led them to become bound tightly in the pocket. In addition, pocket volume calculations showed that the volumes of active site for FOL03 and FOL08 inside the FRα pocket were smaller than the FA-FRα system, indicating strong interactions between the protein active site residues with these new FA analogs compared to FA during the MD simulations.
    Matched MeSH terms: Ligands
  16. Fulltext Docking Studies and Molecular Dynamics Simulation of Ipomoea batatas L. Leaves Compounds as Lipoxygenase (LOX) Inhibitor
    Yeni Y, Supandi S, Dwita LP, Suswandari S, Shaharun MS, Sambudi NS
    J Pharm Bioallied Sci, 2020 Nov;12(Suppl 2):S836-S840.
    PMID: 33828386 DOI: 10.4103/jpbs.JPBS_103_20
    Background: Inflammatory mediators produced by cyclooxygenase (COX) and lipoxygenase (LOX) pathways are responsible for many human diseases, such as cancer, arthritis, and neurological disorders. Flavonoid-containing plants, such as Ipomoea batatas leaves, have shown potential anti-inflammatory activity.

    Objectives: This study aimed to predict the actions of 10 compounds in I. batatas leaves, which are YGM-0a [cyanidin 3-0-sophoroside-5-0-glucosede], YGM-0f [cyanidin 3-O-(2-0-(6-0-(E)-p-coumaroyl-β-D-glucopyranosyl)-β-D-glucopyranoside)-5-0-β-D-glucopyranoside], YGM-1a [cyanidin 3-(6,6'-caffeylp-hydroxybenzoylsophoroside) -5-glucoside], YGM-1b [cyanidin 3-(6,6'-dicaffeylsophor-oside)-5-glucoside], YGM-2 [cyanidin 3-(6-caffeylsophoroside)-5-glucoside], YGM-3 [cyanidin 3-(6,6'-caffeyl-ferulylsophoroside)-5-glucoside], YGM-4b [peonidin 3-(6,6'-dicaffeylsophoroside)-5- glucoside], YGM-5a [peonidin 3-(6,6'-caffeylphydroxybenzo-ylsophoroside)-5-gluco-side], YGM-5b [cyanidin 3-6-caffeylsophoroside)-5-glucosede], and YGM-6 [peonidin 3-(6,6'-caffeylferulylsophoroside)-5-glucoside] as LOX inhibitors, and also predict the stability of ligand-LOX complex.

    Materials and Methods: The compounds were screened through docking studies using PLANTS. Also, the molecular dynamics simulation was conducted using GROMACS at 310K.

    Results: The results showed that the most significant binding affinity toward LOX was shown by YGM-0a and YGM-0a, and the LOX complex in molecular dynamics simulation showed stability for 20 ns.

    Conclusion: Based on Docking Studies and Molecular Dynamics Simulation of I. Batatas Leaves compounds, YGM-0a was shown to be the most probable LOX inhibitor.

    Matched MeSH terms: Ligands
  17. Fulltext Immune Checkpoint Inhibitors in Urothelial Carcinoma: Recommendations for Practical Approaches to PD-L1 and Other Potential Predictive Biomarker Testing
    Lopez-Beltran A, López-Rios F, Montironi R, Wildsmith S, Eckstein M
    Cancers (Basel), 2021 Mar 20;13(6).
    PMID: 33804698 DOI: 10.3390/cancers13061424
    Immuno-oncology (IO) agents (anti-programmed cell death 1 (PD-1) and anti-programmed cell death-ligand 1 (PD-L1)) are approved as first- and second-line treatments for metastatic UC. PD-L1 expression levels in UC tumors help clinicians determine which patients are more likely to respond to IO therapies. Assays for approved IO agents use different antibodies, immunohistochemical protocols, cutoffs (defining "high" vs. "low" PD-L1 expression), and scoring algorithms. The robust control of pre-analytical and analytical standards is needed to obtain high-quality PD-L1 results. To better understand the status and perspectives of biomarker-guided patient selection for anti-PD-1 and anti-PD-L1 agents in UC, three workshops were held from December 2018 to December 2019 in Italy, Malaysia, and Spain. The primary goal was to develop recommendations for best practice approaches to PD-L1 testing in UC. Recommendations pertaining to the interpretation and reporting of the results of PD-L1 assays from experienced pathologists and oncologists from around the globe are included. A test request form for pathology laboratories was developed as a critical first step for oncologists/urologists to encourage communication between clinicians and pathologists, ensuring fast and high-quality test results. In this era of personalized medicine, we briefly discuss novel biomarkers being evaluated for IO agents in UC.
    Matched MeSH terms: Ligands
  18. Fulltext Identification of Potential Inhibitors of 3CL Protease of SARS-CoV-2 From ZINC Database by Molecular Docking-Based Virtual Screening
    Abdusalam AAA, Murugaiyah V
    Front Mol Biosci, 2020;7:603037.
    PMID: 33392261 DOI: 10.3389/fmolb.2020.603037
    The rapid outbreak of Coronavirus Disease 2019 (COVID-19) that was first identified in Wuhan, China is caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The 3CL protease (3CLpro) is the main protease of the SARS-CoV-2, which is responsible for the viral replication and therefore considered as an attractive drug target since to date there is no specific and effective vaccine available against this virus. In this paper, we reported molecular docking-based virtual screening (VS) of 2000 compounds obtained from the ZINC database and 10 FDA-approved (antiviral and anti-malaria) on 3CLpro using AutoDock Vina to find potential inhibitors. The screening results showed that the top four compounds, namely ZINC32960814, ZINC12006217, ZINC03231196, and ZINC33173588 exhibited high affinity at the 3CLpro binding pocket. Their free energy of binding (FEB) were -12.3, -11.9, -11.7, and -11.2 kcal/mol while AutoDock Vina scores were -12.61, -12.32, -12.01, and -11.92 kcal/mol, respectively. These results were better than the co-crystallized ligand N3, whereby its FEB was -7.5 kcal/mol and FDA-approved drugs. Different but stable interactions were obtained between the four identified compounds with the catalytic dyad residues of the 3CLpro. In conclusion, novel 3CLpro inhibitors from the ZINC database were successfully identified using VS and molecular docking approach, fulfilling the Lipinski rule of five, and having low FEB and functional molecular interactions with the target protein. The findings suggests that the identified compounds may serve as potential leads that act as COVID-19 3CLpro inhibitors, worthy for further evaluation and development.
    Matched MeSH terms: Ligands
  19. Fulltext Potential roles of 5-HT3 receptor (5-HT3R) antagonists in modulating the effects of nicotine
    Zulkifli MH, Viswenaden P, Jasamai M, Azmi N, Yaakob NS
    Biomed Pharmacother, 2019 Feb 20;112:108630.
    PMID: 30797147 DOI: 10.1016/j.biopha.2019.108630
    5-HT3R antagonists such as ondansetron, granisetron and tropisetron have been clinically used to treat nausea and vomiting in chemotherapy patients. However, current study and research revealed novel potentials of these ligands in other diseases like inflammation, Alzheimer's, and drug abuse. Towards utilising these drugs as anti-smoking agents to treat nicotine dependence problem, there are conflicting reports regarding the potential of these ligands in modulating the effects of nicotine in both human and animal behavioural studies. This is complicated by the heterogeneity of 5-HT3R itself, cross regulation between nicotinic acetylcholinergic receptor (nAChR) and distinct pharmacological profiles of 5-HT3R antagonists. This review gathered existing studies conducted investigating the potential of "-setron" class of 5-HT3R antagonists in modulating nicotine effects. We proposed that the mechanism where 5-HT3R antagonists mediate the effects of nicotine could be attributed by both direct at 5-HT3R and indirect mechanism in nicotine addiction downstream regulation. The indirect mechanism mediated by the 5-HT3R antagonist could be through α7 nAChR, 5-HT1B receptor (5-HT1BR), 5-HT1C receptor (5-HT1CR), calcineurin activity, p38 MAPK level, PPAR-γ and NF-κβ. Our review suggested that future studies should focus on newer 5-HT3R antagonist with superior pharmacological profile or the one with multitarget action rather than high selectivity at single receptor.
    Matched MeSH terms: Ligands
  20. Converting differential-equation models of biological systems to membrane computing
    Muniyandi RC, Zin AM, Sanders JW
    Biosystems, 2013 Dec;114(3):219-26.
    PMID: 24120990 DOI: 10.1016/j.biosystems.2013.09.008
    This paper presents a method to convert the deterministic, continuous representation of a biological system by ordinary differential equations into a non-deterministic, discrete membrane computation. The dynamics of the membrane computation is governed by rewrite rules operating at certain rates. That has the advantage of applying accurately to small systems, and to expressing rates of change that are determined locally, by region, but not necessary globally. Such spatial information augments the standard differentiable approach to provide a more realistic model. A biological case study of the ligand-receptor network of protein TGF-β is used to validate the effectiveness of the conversion method. It demonstrates the sense in which the behaviours and properties of the system are better preserved in the membrane computing model, suggesting that the proposed conversion method may prove useful for biological systems in particular.
    Matched MeSH terms: Ligands
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