Displaying publications 41 - 60 of 256 in total

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  1. Ajmalicine and its Analogues Against AChE and BuChE for the Management of Alzheimer's Disease: An In-silico Study
    Liu S, Dang M, Lei Y, Ahmad SS, Khalid M, Kamal MA, et al.
    Curr Pharm Des, 2020;26(37):4808-4814.
    PMID: 32264807 DOI: 10.2174/1381612826666200407161842
    BACKGROUND: Alzheimer's disease (AD) is the most well-known reason for disability in persons aged greater than 65 years worldwide. AD influences the part of the brain that controls cognitive and non-cognitive functions.

    OBJECTIVE: The study focuses on the screening of natural compounds for the inhibition of AChE and BuChE using a computational methodology.

    METHODS: We performed a docking-based virtual screening utilizing the 3D structure of AChE and BuChE to search for potential inhibitors for AD. In this work, a screened inhibitor Ajmalicine similarity search was carried out against a natural products database (Super Natural II). Lipinski rule of five was carried out and docking studies were performed between ligands and enzyme using 'Autodock4.2'.

    RESULTS: Two phytochemical compounds SN00288228 and SN00226692 were predicted for the inhibition of AChE and BuChE, respectively. The docking results revealed Ajmalicine, a prominent natural alkaloid, showing promising inhibitory potential against AChE and BuChE with the binding energy of -9.02 and -8.89 kcal/mole, respectively. However, SN00288228- AChE, and SN00226692-BuChE were found to have binding energy -9.88 and -9.54 kcal/mole, respectively. These selected phytochemical compounds showed better interactions in comparison to Ajmalicine with the target molecule.

    CONCLUSION: The current study verifies that SN00288228 and SN00226692 are more capable inhibitors of human AChE and BuChE as compared to Ajmalicine with reference to ΔG values.

    Matched MeSH terms: Ligands
  2. Fulltext The major allergen Der p 2 is a cholesterol binding protein
    Reginald K, Chew FT
    Sci Rep, 2019 02 07;9(1):1556.
    PMID: 30733527 DOI: 10.1038/s41598-018-38313-9
    Der p 2 is a major dust mite allergen and >80% of mite allergic individuals have specific IgE to this allergen. Although it is well characterized in terms of allergenicity, there is still some ambiguity in terms of its biological function. Three-dimensional structural analysis of Der p 2 and its close homologues indicate the presence of a hydrophobic cavity which can potentially bind to lipid molecules. In this study, we aimed to identify the potential ligand of Der p 2. Using a liposome pulldown assay, we show that recombinant Der p 2 binds to liposomes prepared with exogenous cholesterol in a dose dependent fashion. Next, an ELISA based assay using immobilized lipids was used to study binding specificities of other lipid molecules. Cholesterol was the preferred ligand of Der p 2 among 11 different lipids tested. Two homologues of Der p 2, Der f 2 and Der f 22 also bound to cholesterol. Further, using liquid chromatography-mass spectrometry (LC-MS), we confirmed that cholesterol is the natural ligand of Der p 2. Three amino acid residues of Der p 2, V104, V106 and V110 are possible cholesterol binding sites, as alanine mutations of these residues showed a significant decrease in binding (p 
    Matched MeSH terms: Ligands
  3. Synthesis of iron oxide (Fe304) magnetic nanocrystals by green chemistry approach
    Chiu W, Too S, Daud S, Rashid N, Chia M, Rahman S, et al.
    Sains Malaysiana, 2014;43:941-945.
    In the present study, we report the size distribution study on the iron oxide (Fe304) magnetic nanocrystals (Ncs), which have been synthesized by using green chemistry approach with palm-oil based carboxylic compound (oleic acid) as capping ligands . The Fe304 Ncs were prepared by one pot reaction under non-hydrolytic approach. With the assistance of oleic acid that plays the role as effective capping-ligands , we showed that the Fe304 NCs that are highly monodispersed in size and shape can be synthesized by scrupulously controlling the reaction time. The diameter of Fe304 Ncs can be tuned within the range of 4.0-18.0 nm and exhibit very uniform morphology, which are spherical in shape. Current synthetic approach offers a cheap, environmentally benign and excellent repeatability route in large-scale production of high-quality magnetic Fe304 Ncs if compared to the preceding reports.
    Matched MeSH terms: Ligands
  4. Synthesis, characterization, DNA-binding study and anticancer properties of ternary metal(II) complexes of edda and an intercalating ligand
    Ng CH, Kong KC, Von ST, Balraj P, Jensen P, Thirthagiri E, et al.
    Dalton Trans, 2008 Jan 28.
    PMID: 18185860 DOI: 10.1039/b709269e
    A series of ternary metal(ii) complexes {M(phen)(edda); 1a (Cu), 1b (Co), 1c (Zn), 1d (Ni); H(2)edda = N,N(')-ethylenediaminediacetic acid} of N,N'-ethylene-bridged diglycine and 1,10-phenanthroline were synthesized and characterized by elemental analysis, FTIR, UV-visible spectroscopy and magnetic susceptibility measurement. The interaction of these complexes with DNA was investigated using CD and EPR spectroscopy. MTT assay results of 1a-1c , screened on MCF-7 cancer cell lines, show that synergy between the metal and ligands results in significant enhancement of their antiproliferative properties. Preliminary results from apoptosis and cell cycle analyses with flow cytometry are reported. seems to be able to induce cell cycle arrest at G(0)/G(1). The crystal structure of 1a is also included.
    Matched MeSH terms: Ligands
  5. Fulltext Emodin Derivatives as Multi-Target-Directed Ligands Inhibiting Monoamine Oxidase and Antagonizing Vasopressin V1A Receptors
    Paudel P, Shrestha S, Park SE, Seong SH, Fauzi FM, Jung HA, et al.
    ACS Omega, 2020 Oct 20;5(41):26720-26731.
    PMID: 33110998 DOI: 10.1021/acsomega.0c03649
    The brain neurotransmitter level is associated with the pathology of various neurodegenerative diseases, and age-dependent increase in the blood level of vasopressin, human brain monoamine oxidase (hMAO) level, oxidative stress, and imbalance in aminergic signaling are common disease-modifying factors leading to various neurodegenerative disorders. Based on the reports of emodin in hMAO inhibition and antagonist effect on the vasopressin V1A receptor, in this study we synthesized six emodin derivatives and evaluated their effects on MAO activity and G protein-coupled receptors. Among them, 4-hydroxyemodin and 5-hydroxyemodin were potent inhibitors of hMAO, and 2-hydroxyemodin and 5-hydroxyemodin were good V1AR antagonists. In silico molecular docking simulation revealed that the hydroxyl group at C2, C4, and C5 of the respective compounds interacted with prime residues, which corroborates the in vitro effect. Likewise, these three derivatives were predicted to have good drug-like properties. Overall, our study demonstrates that the hydroxyl derivatives of emodin are multi-target-directed ligands that may act as leads for the design and development of a therapy for central nervous system disorders.
    Matched MeSH terms: Ligands
  6. Carbohydrazones as new class of carbonic anhydrase inhibitors: Synthesis, kinetics, and ligand docking studies
    Iqbal S, Saleem M, Azim MK, Taha M, Salar U, Khan KM, et al.
    Bioorg Chem, 2017 06;72:89-101.
    PMID: 28390994 DOI: 10.1016/j.bioorg.2017.03.014
    Discovery and development of carbonic anhydrase inhibitors is crucial for their clinical use as antiepileptic, diurectic and antiglaucoma agents. Keeping this in mind, we have synthesized carbohydrazones 1-27 and evaluated them for their in vitro carbonic anhydrase inhibitory potential. Out of twenty-seven compounds, compounds 1 (IC50=1.33±0.01µM), 2 (IC50=1.85±0.24µM), 3 (IC50=1.37±0.06µM), and 9 (IC50=1.46±0.12µM) have showed carbonic anhydrase inhibition better than the standard drug zonisamide (IC50=1.86±0.03µM). Moreover, compounds 4 (IC50=2.32±0.04µM), 5 (IC50=3.96±0.35µM), 7 (IC50=2.33±0.02µM), and 8 (IC50=2.67±0.01µM) showed good inhibitory activity. Cheminformatic analysis has shown that compounds 1 and 2 possess lead-like properties. In addition, kinetic and molecular docking studies were also performed to investigate the binding interaction between carbohydrazones and carbonic anhydrase enzyme. This study has identified a novel and potent class of carbonic anhydrase inhibitors with the potential to be investigated further.
    Matched MeSH terms: Ligands
  7. Fulltext In Silico Discovery of Potential Uridine-Cytidine Kinase 2 Inhibitors from the Rhizome of Alpinia mutica
    Malami I, Abdul AB, Abdullah R, Bt Kassim NK, Waziri P, Christopher Etti I
    Molecules, 2016 Apr 08;21(4):417.
    PMID: 27070566 DOI: 10.3390/molecules21040417
    Uridine-cytidine kinase 2 is implicated in uncontrolled proliferation of abnormal cells and it is a hallmark of cancer, therefore, there is need for effective inhibitors of this key enzyme. In this study, we employed the used of in silico studies to find effective UCK2 inhibitors of natural origin using bioinformatics tools. An in vitro kinase assay was established by measuring the amount of ADP production in the presence of ATP and 5-fluorouridine as a substrate. Molecular docking studies revealed an interesting ligand interaction with the UCK2 protein for both flavokawain B and alpinetin. Both compounds were found to reduce ADP production, possibly by inhibiting UCK2 activity in vitro. In conclusion, we have identified flavokawain B and alpinetin as potential natural UCK2 inhibitors as determined by their interactions with UCK2 protein using in silico molecular docking studies. This can provide information to identify lead candidates for further drug design and development.
    Matched MeSH terms: Ligands
  8. Structure-based identification of aporphines with selective 5-HT(2A) receptor-binding activity
    Munusamy V, Yap BK, Buckle MJ, Doughty SW, Chung LY
    Chem Biol Drug Des, 2013 Feb;81(2):250-6.
    PMID: 23039820 DOI: 10.1111/cbdd.12069
    Selective blockade of the serotonin 5-HT(2A) receptor is a useful therapeutic approach for a number of disorders, including schizophrenia, insomnia and ischaemic heart disease. A series of aporphines were docked into a homology model of the rat 5-HT(2A) receptor using AutoDock. Selected compounds with high in silico binding affinities were screened in vitro using radioligand-binding assays against rat serotonin (5-HT(1A) and 5-HT(2A)) and dopamine (D1 and D2) receptors. (R)-Roemerine and (±)-nuciferine were found to have high affinity for the 5-HT(2A) receptor (K(i) = 62 and 139 nM, respectively), with (R)-roemerine showing 20- to 400-fold selectivity for the 5-HT(2A) receptor over the 5-HT(1A), D1 and D2 receptors. Investigation into the ligand-receptor interactions suggested that the selectivity of (R)-roemerine is due to it having stronger H-bonding and dipole-dipole interactions with several of the key residues in the 5-HT(2A) receptor-binding site.
    Matched MeSH terms: Ligands
  9. Tribenzyltin carboxylates as anticancer drug candidates: Effect on the cytotoxicity, motility and invasiveness of breast cancer cell lines
    Anasamy T, Thy CK, Lo KM, Chee CF, Yeap SK, Kamalidehghan B, et al.
    Eur J Med Chem, 2017 Jan 05;125:770-783.
    PMID: 27723565 DOI: 10.1016/j.ejmech.2016.09.061
    This study seeks to investigate the relationship between the structural modification and bioactivity of a series of tribenzyltin complexes with different ligands and substitutions. Complexation with the N,N-diisopropylcarbamothioylsulfanylacetate or isonicotinate ligands enhanced the anticancer properties of tribenzyltin compounds via delayed cancer cell-cycle progression, caspase-dependent apoptosis induction, and significant reduction in cell motility, migration and invasion. Halogenation of the benzyl ring improved the anticancer effects of the tribenzyltin compounds with the N,N-diisopropylcarbamothioylsulfanylacetate ligand. These compounds also demonstrated far greater anticancer effects and selectivity than cisplatin and doxorubicin, which provides a rationale for their further development as anticancer agents.
    Matched MeSH terms: Ligands
  10. In-silico selection employing rigid docking and molecular dynamic simulation in selecting DNA aptamers against androgen receptor
    Thevendran R, Tang TH, Citartan M
    Biotechnol J, 2023 Apr;18(4):e2200092.
    PMID: 36735817 DOI: 10.1002/biot.202200092
    Aptamers are a class of single-stranded (ss) nucleic acid molecules generated through Systematic Evolution of Ligands by Exponential Enrichment (SELEX) that involves iterations of time-consuming and tedious selection, amplification, and enrichment steps. To compensate for the drawbacks of conventional SELEX, we have devised an in-silico methodology that facilitates a cost-effective and facile manner of aptamer selection. Here, we report the isolation of DNA aptamers against androgen receptors (ARs) using androgen response elements (ARE) that possess natural affinity toward AR. A virtual library of ARE sequences was prepared and subjected to a stringent selection criterion to generate a sequence pool having stable hairpin conformations and high GC content. The 3D-structures of the selected ss AREs were modeled and screened through rigid docking and molecular dynamic (MD) simulation to examine their potency as potential AR binders. The predicted sequences were further validated using direct enzyme-linked aptasorbent assay (ELASA), which includes the measurement of their binding affinity, specificity, and target discrimination properties under complex biological enviroments. A short, 15 nucleotides (nts), ssDNA aptamer, termed ARapt1 with the estimated Kd value of 5.5 ± 3 nm, was chosen as the most prominent aptamer against AR based on the coherence of both the in-silico and in-vitro evaluation results. The high target-binding affinity and selectivity of ARapt1 signify its potential use as a versatile tool in diagnostic applications relevant to prostate cancer and related diseases.
    Matched MeSH terms: Ligands
  11. Lung cancer: active therapeutic targeting and inhalational nanoproduct design
    Alhajj N, Chee CF, Wong TW, Rahman NA, Abu Kasim NH, Colombo P
    Expert Opin Drug Deliv, 2018 12;15(12):1223-1247.
    PMID: 30422017 DOI: 10.1080/17425247.2018.1547280
    INTRODUCTION: Pulmonary drug delivery is organ-specific and benefits local drug action for lung cancer. The use of nanotechnology and targeting ligand enables cellular-specific drug action. Combination approaches increase therapeutic efficacy and reduce adverse effects of cancer chemotherapeutics that have narrow therapeutic index window and high cytotoxicity levels. The current progress of inhaled cancer chemotherapeutics has not been examined with respect to targeting strategy and clinical application potential.

    AREAS COVERED: This review examines the state of the art in passive (processing and formulation) and active (targeting ligand and receptor binding) technologies in association with the use of nanocarrier to combat lung cancer. It highlights routes to equip nanocarrier with targeting ligands as a function of the chemistry of participating biomolecules and challenges in inhalational nanoproduct development and clinical applications. Both research and review articles were examined using the Scopus, Elsevier, Web of Science, Chemical Abstracts, Medline, CASREACT, CHEMCATS, and CHEMLIST database with the majority of information retrieved between those of 2000-2018.

    EXPERT COMMENTARY: The therapeutic efficacy of targeting ligand-decorated nanocarriers needs to be demonstrated in vivo in the form of finished inhalational products. Their inhalation efficiency and medical responses require further examination. Clinical application of inhaled nanocancer chemotherapeutics is premature.

    Matched MeSH terms: Ligands
  12. SELEX Modifications and Bioanalytical Techniques for Aptamer-Target Binding Characterization
    Tan SY, Acquah C, Sidhu A, Ongkudon CM, Yon LS, Danquah MK
    Crit Rev Anal Chem, 2016 Nov;46(6):521-37.
    PMID: 26980177 DOI: 10.1080/10408347.2016.1157014
    The quest to improve the detection of biomolecules and cells in health and life sciences has led to the discovery and characterization of various affinity bioprobes. Libraries of synthetic oligonucleotides (ssDNA/ssRNA) with randomized sequences are employed during Systematic Evolution of Ligands by Exponential Enrichment (SELEX) to select highly specific affinity probes called aptamers. With much focus on the generation of aptamers for a variety of target molecules, conventional SELEX protocols have been modified to develop new and improved SELEX protocols yielding highly specific and stable aptamers. Various techniques have been used to analyze the binding interactions between aptamers and their cognate molecules with associated merits and limitations. This article comprehensively reviews research advancements in the generation of aptamers, analyses physicochemical conditions affecting their binding characteristics to cellular and biomolecular targets, and discusses various field applications of aptameric binding. Biophysical techniques employed in the characterization of the molecular and binding features of aptamers to their cognate targets are also discussed.
    Matched MeSH terms: Ligands
  13. Fulltext Characterisation of aptamer-anchored poly(EDMA-co-GMA) monolith for high throughput affinity binding
    Acquah C, Chan YW, Pan S, Yon LS, Ongkudon CM, Guo H, et al.
    Sci Rep, 2019 10 10;9(1):14501.
    PMID: 31601836 DOI: 10.1038/s41598-019-50862-1
    Immobilisation of aptameric ligands on solid stationary supports for effective binding of target molecules requires understanding of the relationship between aptamer-polymer interactions and the conditions governing the mass transfer of the binding process. Herein, key process parameters affecting the molecular anchoring of a thrombin-binding aptamer (TBA) onto polymethacrylate monolith pore surface, and the binding characteristics of the resulting macroporous aptasensor were investigated. Molecular dynamics (MD) simulations of the TBA-thrombin binding indicated enhanced Guanine 4 (G4) structural stability of TBA upon interaction with thrombin in an ionic environment. Fourier-transform infrared spectroscopy and thermogravimetric analyses were used to characterise the available functional groups and thermo-molecular stability of the immobilised polymer generated with Schiff-base activation and immobilisation scheme. The initial degradation temperature of the polymethacrylate stationary support increased with each step of the Schiff-base process: poly(Ethylene glycol Dimethacrylate-co-Glycidyl methacrylate) or poly(EDMA-co-GMA) [196.0 °C (±1.8)]; poly(EDMA-co-GMA)-Ethylenediamine [235.9 °C (±6.1)]; poly(EDMA-co-GMA)-Ethylenediamine-Glutaraldehyde [255.4 °C (±2.7)]; and aptamer-modified monolith [273.7 °C (±2.5)]. These initial temperature increments reflected in the associated endothermic energies were determined with differential scanning calorimetry. The aptameric ligand density obtained after immobilisation was 480 pmol/μL. Increase in pH and ionic concentration affected the surface charge distribution and the binding characteristics of the aptamer-modified disk-monoliths, resulting in the optimum binding pH and ionic concentration of 8.0 and 5 mM Mg2+, respectively. These results are critical in understanding and setting parametric constraints indispensable to develop and enhance the performance of aptasensors.
    Matched MeSH terms: Ligands
  14. Aptamers: an emerging class of bioaffinity ligands in bioactive peptide applications
    Acquah C, Agyei D, Obeng EM, Pan S, Tan KX, Danquah MK
    Crit Rev Food Sci Nutr, 2020;60(7):1195-1206.
    PMID: 30714390 DOI: 10.1080/10408398.2018.1564234
    The food and health applications of bioactive peptides have grown remarkably in the past few decades. Current elucidations have shown that bioactive peptides have unique structural arrangement of amino acids, conferring distinct functionalities, and molecular affinity characteristics. However, whereas interest in the biological potency of bioactive peptides has grown, cost-effective techniques for monitoring the structural changes in these peptides and how these changes affect the biological properties have not grown at the same rate. Due to the high binding affinity of aptamers for other biomolecules, they have a huge potential for use in tracking the structural, conformational, and compositional changes in bioactive peptides. This review provides an overview of bioactive peptides and their essential structure-activity relationship. The review further highlights on the types and methods of synthesis of aptamers before the discussion of the prospects, merits, and challenges in the use of aptamers for bioaffinity interactions with bioactive peptides.
    Matched MeSH terms: Ligands
  15. Synthesis, structure, solution behavior, reactivity and biological evaluation of oxidovanadium(iv/v) thiosemicarbazone complexes
    Saswati, Adão P, Majumder S, Dash SP, Roy S, Kuznetsov ML, et al.
    Dalton Trans, 2018 Aug 21;47(33):11358-11374.
    PMID: 30059099 DOI: 10.1039/c8dt01668b
    The synthesis and characterization of an oxidovanadium(iv) [VIVO(L)(acac)] (1) and of two dioxidovanadium(v) [VVO2(L')] (2) and [VVO2(L)] (2a) complexes of the Schiff base formed from the reaction of 4-(p-fluorophenyl) thiosemicarbazone with pyridine-2-aldehyde (HL) are described. The oxidovanadium(iv) species [VIVO(L)(acac)] (1) was synthesized by the reaction of VIVO(acac)2 with the thiosemicarbazone HL in refluxing ethanol. The recrystallization of [VIVO(L)(acac)] (1) in DMF, CH3CN or EtOH gave the same product i.e. the dioxidovanadium(v) complex [VVO2(L)] (2a); however, upon recrystallization of 1 in DMSO a distinct compound [VVO2(L')] (2) was formed, wherein the original ligand L- is transformed to a rearranged one, L'-. In the presence of DMSO the ligand in complex 1 is found to undergo methylation at the carbon centre attached to imine nitrogen (aldimine) and transformed to the corresponding VVO2-species through in situ reaction. The synthesized HL and the metal complexes were characterized by elemental analysis, IR, UV-Vis, NMR and EPR spectroscopy. The molecular structure of [VVO2(L')] (2) was determined by single crystal X-ray crystallography. The methylation of various other ligands and complexes prepared from different vanadium precursors under similar reaction conditions was also attempted and it was confirmed that the imine methylation observed is both ligand and metal precursor specific. Complexes 1 and 2 show in vitro insulin-like activity against insulin responsive L6 myoblast cells, higher than VIVO(acac)2, with complex 1 being more potent. In addition, the in vitro cytotoxicity studies of HL, and of complexes 1 and 2 against the MCF-7 and Vero cell lines were also done. The ligand is not cytotoxic and complex 2 is significantly more cytotoxic than 1. DAPI staining experiments indicate that an increase in the time of incubation and an increase of concentration of the complexes lead to the increase in cell death.
    Matched MeSH terms: Ligands
  16. 1,3,5-Triazine-based analogues of purine: from isosteres to privileged scaffolds in medicinal chemistry
    Lim FP, Dolzhenko AV
    Eur J Med Chem, 2014 Oct 6;85:371-90.
    PMID: 25105925 DOI: 10.1016/j.ejmech.2014.07.112
    Purines can be considered as the most ubiquitous and functional N-heterocyclic compounds in nature. Structural modifications of natural purines, particularly using isosteric ring systems, have been in the focus of many drug discovery programs. Fusion of 1,3,5-triazine ring with pyrrole, pyrazole, imidazole, 1,2,3-triazole or 1,2,4-triazole results in seven bicyclic heterocyclic systems isosteric to purine. Application of the isosterism concept for the development of new compounds with therapeutic potential in areas involving purinergic regulation or purine metabolism led to significant advances in medicinal chemistry of the azolo[1,3,5]triazines. These 1,3,5-triazine-based purine-like scaffolds significantly increase level of molecular diversity and allow covering chemical space in the important areas of medicinal chemistry. Some of these azolo[1,3,5]triazine systems have become privileged scaffolds in the development of inhibitors of various kinases, phosphodiesterase, xanthine oxidase, and thymidine phosphorylase, antagonists of adenosine and corticotropin-releasing hormone receptors, anticancer and antiviral agents.
    Matched MeSH terms: Ligands
  17. Molecular dynamics simulations of the adenosine A2a receptor: structural stability, sampling, and convergence
    Ng HW, Laughton CA, Doughty SW
    J Chem Inf Model, 2013 May 24;53(5):1168-78.
    PMID: 23514445 DOI: 10.1021/ci300610w
    Molecular dynamics (MD) simulations of membrane-embedded G-protein coupled receptors (GPCRs) have rapidly gained popularity among the molecular simulation community in recent years, a trend which has an obvious link to the tremendous pharmaceutical importance of this group of receptors and the increasing availability of crystal structures. In view of the widespread use of this technique, it is of fundamental importance to ensure the reliability and robustness of the methodologies so they yield valid results and enable sufficiently accurate predictions to be made. In this work, 200 ns simulations of the A2a adenosine receptor (A2a AR) have been produced and evaluated in the light of these requirements. The conformational dynamics of the target protein, as obtained from replicate simulations in both the presence and absence of an inverse agonist ligand (ZM241385), have been investigated and compared using principal component analysis (PCA). Results show that, on this time scale, convergence of the replicates is not readily evident and dependent on the types of the protein motions considered. Thus rates of inter- as opposed to intrahelical relaxation and sampling can be different. When studied individually, we find that helices III and IV have noticeably greater stability than helices I, II, V, VI, and VII in the apo form. The addition of the inverse agonist ligand greatly improves the stability of all helices.
    Matched MeSH terms: Ligands
  18. Assessing GPCR homology models constructed from templates of various transmembrane sequence identities: Binding mode prediction and docking enrichment
    Loo JSE, Emtage AL, Ng KW, Yong ASJ, Doughty SW
    J Mol Graph Model, 2017 Dec 29;80:38-47.
    PMID: 29306746 DOI: 10.1016/j.jmgm.2017.12.017
    GPCR crystal structures have become more readily accessible in recent years. However, homology models of GPCRs continue to play an important role as many GPCR structures remain unsolved. The new crystal structures now available provide not only additional templates for homology modelling but also the opportunity to assess the performance of homology models against their respective crystal structures and gain insight into the performance of such models. In this study we have constructed homology models from templates of various transmembrane sequence identities for eight GPCR targets to better understand the relationship between transmembrane sequence identity and model quality. Model quality was assessed relative to the crystal structure in terms of structural accuracy as well as performance in two typical structure-based drug design applications: ligand binding pose prediction and docking enrichment in virtual screening. Crystal structures significantly outperformed homology models in both assessments. Accurate ligand binding pose prediction was possible but difficult to achieve using homology models, even with the use of induced fit docking. In virtual screening using homology models still conferred significant enrichment compared to random selection, with a clear benefit also observed in using models optimized through induced fit docking. Our results indicate that while homology models that are reasonably accurate structurally can be constructed, without significant refinement homology models will be outperformed by crystal structures in ligand binding pose prediction and docking enrichment regardless of the template used, primarily due to the extremely high level of structural accuracy needed for such applications.
    Matched MeSH terms: Ligands
  19. Fulltext Peroxisome proliferator-activated receptor gamma: promising target in glioblastoma
    Gupta G, Singhvi G, Chellappan DK, Sharma S, Mishra A, Dahiya R, et al.
    Panminerva Med, 2018 Sep;60(3):109-116.
    PMID: 30176701 DOI: 10.23736/S0031-0808.18.03462-6
    Glioblastoma, also known as glioblastoma multiforme, is the most common and worldwide-spread cancer that begins within the brain. Glioblastomas represent 15% of brain tumors. The most common length of survival following diagnosis is 12 to 14 months with less than 3% to 5% of people surviving longer than five years. Without treatment, survival is typically 3 months. Among all receptors, special attention has been focused on the role of peroxisome proliferator-activated receptors (PPARs) in glioblastoma. PPARs are ligand-activated intracellular transcription factors. The PPAR subfamily consists of three subtypes encoded by distinct genes named PPARα, PPARβ/δ, and PPARγ. PPARγ is the most extensively studied subtype of PPAR. There has been interesting preliminary evidence suggesting that diabetic patients receiving PPARγ agonists, a group of anti-diabetics, thiazolidinedione drugs, have an increased median survival for glioblastoma. In this paper, the recent progresses in understanding the potential mechanism of PPARγ in glioblastoma are summarized.
    Matched MeSH terms: Ligands
  20. 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
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