Displaying publications 101 - 120 of 262 in total

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  1. Fulltext Synthesis, Characterization and Biological Evaluation of New 3,5-Disubstituted-Pyrazoline Derivatives as Potential Anti-Mycobacterium tuberculosis H37Ra Compounds
    Wong KT, Osman H, Parumasivam T, Supratman U, Che Omar MT, Azmi MN
    Molecules, 2021 Apr 05;26(7).
    PMID: 33916423 DOI: 10.3390/molecules26072081
    A total of fourteen pyrazoline derivatives were synthesized through cyclo-condensation reactions by chalcone derivatives with different types of semicarbazide. These compounds were characterized by IR, 1D-NMR (1H, 13C and Distortionless Enhancement by Polarization Transfer - DEPT-135) and 2D-NMR (COSY, HSQC and HMBC) as well as mass spectroscopy analysis (HRMS). The synthesized compounds were tested for their antituberculosis activity against Mycobacterium tuberculosis H37Ra in vitro. Based on this activity, compound 4a showed the most potent inhibitory activity, with a minimum inhibitory concentration (MIC) value of 17 μM. In addition, six other synthesized compounds, 5a and 5c-5g, exhibited moderate activity, with MIC ranges between 60 μM to 140 μM. Compound 4a showed good bactericidal activity with a minimum bactericidal concentration (MBC) value of 34 μM against Mycobacterium tuberculosis H37Ra. Molecular docking studies for compound 4a on alpha-sterol demethylase was done to understand and explore ligand-receptor interactions, and to hypothesize potential refinements for the compound.
    Matched MeSH terms: Ligands
  2. Fulltext Discovery of HIV entry inhibitors via a hybrid CXCR4 and CCR5 receptor pharmacophore-based virtual screening approach
    Mirza MU, Saadabadi A, Vanmeert M, Salo-Ahen OMH, Abdullah I, Claes S, et al.
    Eur J Pharm Sci, 2020 Dec 01;155:105537.
    PMID: 32890663 DOI: 10.1016/j.ejps.2020.105537
    Chemokine receptors are key regulators of cell migration in terms of immunity and inflammation. Among these, CCR5 and CXCR4 play pivotal roles in cancer metastasis and HIV-1 transmission and infection. They act as essential co-receptors for HIV and furnish a route to the cell entry. In particular, inhibition of either CCR5 or CXCR4 leads very often the virus to shift to a more virulent dual-tropic strain. Therefore, dual receptor inhibition might improve the therapeutic strategies against HIV. In this study, we aimed to discover selective CCR5, CXCR4, and dual CCR5/CXCR4 antagonists using both receptor- and ligand-based computational methods. We employed this approach to fully incorporate the interaction attributes of the binding pocket together with molecular dynamics (MD) simulations and binding free energy calculations. The best hits were evaluated for their anti-HIV-1 activity against CXCR4- and CCR5-specific NL4.3 and BaL strains. Moreover, the Ca2+ mobilization assay was used to evaluate their antagonistic activity. From the 27 tested compounds, three were identified as inhibitors: compounds 27 (CCR5), 6 (CXCR4) and 3 (dual) with IC50 values ranging from 10.64 to 64.56 μM. The binding mode analysis suggests that the active compounds form a salt bridge with the glutamates and π-stacking interactions with the aromatic side chains binding site residues of the respective co-receptor. The presented hierarchical virtual screening approach provides essential aspects in identifying potential antagonists in terms of selectivity against a specific co-receptor. The compounds having multiple heterocyclic nitrogen atoms proved to be relatively more specific towards CXCR4 inhibition as compared to CCR5. The identified compounds serve as a starting point for further development of HIV entry inhibitors through synthesis and quantitative structure-activity relationship studies.
    Matched MeSH terms: Ligands
  3. Ion-Imprinted Polymer for Selective Separation of Cerium(III) Ions from Rare Earth Mixture
    Rahman ML, Puah PY, Sarjadi MS, Arshad SE, Musta B, Sarkar SM
    J Nanosci Nanotechnol, 2019 09 01;19(9):5796-5802.
    PMID: 30961741 DOI: 10.1166/jnn.2019.16538
    Ion-imprinting polymers (IIPs) materials draw the great recognition because of the powerful selectivity to the desired metal ions. Therefore, the ion-imprinting polymer (Ce-IIP) was prepared by using cerium metal with amidoxime ligand as the complexing agent, in addition ethylene glycol dimethacrylate (EGDMA) and 2,2-azobisisobutyronitrile (AIBN) are crosslinking agent and free radical initiator, respectively. Aqueous HCl was applied to leach the cerium ions from the imprinted polymer for the creation of cavities of template, which is utilized for further cerium ions adsorption with high selectivity. The Ce-IIP was characterized by using ICP-MS, FE-SEM and also solid state analysis by UV-vis NIR spectroscopy. FT-IR study confirmed the complexation of the Ce-IIP was successful. The optimum pH was found to be 6 and the highest adsorption capacity was estimated about 145 mg g-1. Thus, the prepared Ce-IIP gave very good selectivity to cerium ions in the presence of lanthanide ions and also Ce-IIP can be reused 10 times without a substantial loss in adsorption capacity.
    Matched MeSH terms: Ligands
  4. Fulltext Synthesis and characterization of Pd(II) and Ni(II) complexes of Schiff bases and catalytic activity of Pd(II) complexes
    Amalina Mohd Tajuddin, Hadariah Bahron, Shahrul Nizam Ahmad
    Scientific Research Journal, 2015;12(2):0-0.
    MyJurnal
    Six new Pd(II) and Ni(II) metal complexes of N, O-bidentate (L1, L2) and ONNO-tetradentate (L3) Schiff base ligands have been synthesized. The compounds were characterized via various physicochemical and spectroscopic techniques namely elemental analysis (CHN), FT-IR, 1H and 13C NMR as well as magnetic susceptibility measurement. All complexes showed diamagnetism indicating that they are square planar complexes. Catalytic performance of Pd(L1)2 and Pd(L2)2 were investigated for Heck cross-coupling reaction under optimum operating parameters, monitored using GC-FID for 6 h of reaction time in inert conditions. High catalytic activities of up to 90% were observed in the presence of triethylamine as base and DMA as solvent at 100oC with 1 mmol% catalyst loading. The mechanism of catalyzed Heck reaction is proposed to go through a series of conversion of Pd(0)/Pd(II).
    Matched MeSH terms: Ligands
  5. Fulltext Absence of nucleotide alteration in region of exon 34 of NOTCH1 and NOTCH2 receptor genes analysed in oral cancer samples: a preliminary observation
    Nor Nasyitah Ismail, Khairani Idah Mokhtar
    Archives of Orofacial Sciences, 2010;5(1):17-23.
    MyJurnal
    Oral cancer is one of the common cancer cases identified in the developing countries. Genetic mutation and overexpression of certain genes and proteins have been associated in the development of this cancer. Notch signalling pathway is normally involved in controlling the development process of vertebrates and invertebrates; however, deregulation of this pathway was found to be responsible in the formation of certain cancers including oral cancers. Activation of this pathway requires binding of the ligands to its receptors. Four NOTCH receptors (NOTCH 1, 2, 3 and 4) have been identified in mammals. Disruptions within these molecules might interfere with the normal functions of Notch signalling pathway. Hence, this study was conducted to detect mutations of NOTCH1 and NOTCH2 receptor genes which might be occurring in the oral cancer cases obtained from the local population. DNA extracted from fresh-frozen tissue biopsy of the tongue and buccal mucosa from 10 confirmed cases of oral cancer were subjected for polymerase chain reaction (PCR) amplification using the specific sets of primers. The PCR products were sent for sequencing before final results were analysed.
    Due to time and cost limitation, only two out of four NOTCH receptor genes; NOTCH1 and NOTCH2, were used in this analysis. The results revealed absence of nucleotide changes for both NOTCH receptor genes amplified from these oral cancer samples. More samples and further analysis looking into other regions in these genes are required to conclude the involvement of NOTCH receptor genes mutation in causing oral cancer.
    Matched MeSH terms: Ligands
  6. Fulltext Synthesis, enzyme inhibitory kinetics mechanism and computational study of N-(4-methoxyphenethyl)-N-(substituted)-4-methylbenzenesulfonamides as novel therapeutic agents for Alzheimer's disease
    Abbasi MA, Hassan M, Aziz-Ur-Rehman, Siddiqui SZ, Shah SAA, Raza H, et al.
    PeerJ, 2018;6:e4962.
    PMID: 29967717 DOI: 10.7717/peerj.4962
    The present study comprises the synthesis of a new series of sulfonamides derived from 4-methoxyphenethylamine (1). The synthesis was initiated by the reaction of 1 with 4-methylbenzenesulfonyl chloride (2) in aqueous sodium carbonate solution at pH 9 to yield N-(4-methoxyphenethyl)-4-methylbenzensulfonamide (3).This parent molecule 3 was subsequently treated with various alkyl/aralkyl halides, (4a-j), using N,N-dimethylformamide (DMF) as solvent and LiH as activator to produce a series of new N-(4-methoxyphenethyl)-N-(substituted)-4-methylbenzenesulfonamides (5a-j). The structural characterization of these derivatives was carried out by spectroscopic techniques like IR, 1H-NMR, and 13C-NMR. The elemental analysis data was also coherent with spectral data of these molecules. The inhibitory effects on acetylcholinesterase and DPPH were evaluated and it was observed that N-(4-Methoxyphenethyl)-4-methyl-N-(2-propyl)benzensulfonamide (5c) showed acetylcholinesterase inhibitory activity 0.075 ± 0.001 (IC50 0.075 ± 0.001 µM) comparable to Neostigmine methylsulfate (IC50 2.038 ± 0.039 µM).The docking studies of synthesized ligands 5a-j were also carried out against acetylcholinesterase (PDBID 4PQE) to compare the binding affinities with IC50 values. The kinetic mechanism analyzed by Lineweaver-Burk plots demonstrated that compound (5c) inhibits the acetylcholinesterase competitively to form an enzyme inhibitor complex. The inhibition constants Ki calculated from Dixon plots for compound (5c) is 2.5 µM. It was also found from kinetic analysis that derivative 5c irreversible enzyme inhibitor complex. It is proposed on the basis of our investigation that title compound 5c may serve as lead structure for the design of more potent acetylcholinesterase inhibitors.
    Matched MeSH terms: Ligands
  7. Flurbiprofen derivatives as novel α-amylase inhibitors: Biology-oriented drug synthesis (BIODS), in vitro, and in silico evaluation
    Khan M, Alam A, Khan KM, Salar U, Chigurupati S, Wadood A, et al.
    Bioorg Chem, 2018 12;81:157-167.
    PMID: 30125730 DOI: 10.1016/j.bioorg.2018.07.038
    Novel derivatives of flurbiprofen 1-18 including flurbiprofen hydrazide 1, substituted aroyl hydrazides 2-9, 2-mercapto oxadiazole derivative 10, phenacyl substituted 2-mercapto oxadiazole derivatives 11-15, and benzyl substituted 2-mercapto oxadiazole derivatives 16-18 were synthesized and characterized by EI-MS, 1H and 13C NMR spectroscopic techniques. All derivatives 1-18 were screened for α-amylase inhibitory activity and demonstrated a varying degree of potential ranging from IC50 = 1.04 ± 0.3 to 2.41 ± 0.09 µM as compared to the standard acarbose (IC50 = 0.9 ± 0.04 µM). Out of eighteen compounds, derivatives 2 (IC50 = 1.69 ± 0.1 µM), 3 (IC50 = 1.04 ± 0.3 µM), 9 (IC50 = 1.25 ± 1.05 µM), and 13 (IC50 = 1.6 ± 0.18 µM) found to be excellent inhibitors while rest of the compounds demonstrated comparable inhibition potential. A limited structure-activity relationship (SAR) was established by looking at the varying structural features of the library. In addition to that, in silico study was conducted to understand the binding interactions of the compounds (ligands) with the active site of α-amylase enzyme.
    Matched MeSH terms: Ligands
  8. Fulltext Analysis of the Binding of Aripiprazole to Human Serum Albumin: The Importance of a Chloro-Group in the Chemical Structure
    Sakurama K, Kawai A, Tuan Giam Chuang V, Kanamori Y, Osa M, Taguchi K, et al.
    ACS Omega, 2018 Oct 31;3(10):13790-13797.
    PMID: 30411049 DOI: 10.1021/acsomega.8b02057
    Aripiprazole (ARP), a quinolinone derivative, is an atypical antipsychotic drug that is used in the treatment of schizophrenia. ARP has an extensive distribution and more than 99% of the ARP and dehydro-ARP, the main active metabolite, is bound to plasma proteins. However, information regarding the protein binding of ARP is limited. In this study, we report on a systematic study of the protein binding of ARP. The interaction of ARP and structurally related compounds with human serum albumin (HSA) was examined using equilibrium dialysis, circular dichroism (CD) spectroscopy, fluorescent probe displacement, and an X-ray crystallographic analysis. The binding affinities (nK) for ARP and its main metabolite, dehydro-ARP with HSA were found to be significantly higher than other structurally related compounds. The results of equilibrium dialysis experiments and CD spectral data indicated that the chloro-group linked to the phenylpiperazine ring in the ARP molecule plays a major role in the binding of these ligands to HSA. Furthermore, fluorescent probe displacement results indicated that ARP appears to bind at the site II pocket in subdomain III. A detailed CD spectral analysis suggests that the chloro-group linked to the phenylpiperazine ring may control the geometry of the ARP molecule when binding in the site II binding pocket. X-ray crystallographic analysis of the ARP-HSA complex revealed that the distance between the chlorine atom at the 3-positon of dichlorophenyl-piperazine on ARP and the sulfur atom of Cys392 in HSA was 3.4-3.6 Å. A similar halogen bond interaction has also been observed in the HSA structure complexed with diazepam, which also contains a chloro-group. Thus, the mechanism responsible for the binding of ARP to a protein elucidated here should be relevant for assessing the pharmacokinetics and pharmacodynamics of ARP in various clinical situations and for designing new drugs.
    Matched MeSH terms: Ligands
  9. A novel ruthenium-tungsten bimetallic complex dye-sensitizer for photoelectrochemical cells application
    Khuzaimah Arifin, Wan Ramli Wan Daud, Mohammad B. Kassim
    Sains Malaysiana, 2014;43:95-101.
    A novel bimetallic double thiocyanate-bridged ruthenium and tungsten metal complex containing bipyridyl and dithiolene co-ligands was synthesized and the behavior of the complex as a dye-sensitizer for a photoelectrochemical (PEG) cell for a direct water splitting reaction was investigated. The ligands and metal complexes were characterized on the basis of elemental analysis as well as uv-Vis, Fourier transform infrared ( Pim) and nuclear magnetic resonance (11I and 13C NMR) spectroscopy. Cyclic voltammetry of the bimetallic complex showed multiple redox couples, in which half potentials E 112 at 0 .625 , 0.05 and 0.61 V were assigned as the formal redox processes of Ru(III)IRu(II) reduction, W(IV)IW(V) and W(V)IW(VI) oxidations, respectively. Photocurrent measurements were performed in homogeneous system and TiO2 was used as the photoanode for photocurrent measurements. Current density generated by the bimetallic complex was higher than that of N3 commercial dye which suggested that the bimetallic complex donated more electrons to the semiconductor.
    Matched MeSH terms: Ligands
  10. Computer-Aided Drug Discovery (CADD) Approaches for the Management of Neuropathic Pain
    Ramesh M, Muthuraman A
    Curr Top Med Chem, 2021;21(32):2856-2868.
    PMID: 34809547 DOI: 10.2174/1568026621666211122161932
    Neuropathic pain occurs due to physical damage, injury, or dysfunction of neuronal fibers. The pathophysiology of neuropathic pain is too complex. Therefore, an accurate and reliable prediction of the appropriate hits/ligands for the treatment of neuropathic pain is a challenging process. However, computer-aided drug discovery approaches contributed significantly to discovering newer hits/ligands for the treatment of neuropathic pain. The computational approaches like homology modeling, induced-fit molecular docking, structure-activity relationships, metadynamics, and virtual screening were cited in the literature for the identification of potential hit molecules against neuropathic pain. These hit molecules act as inducible nitric oxide synthase inhibitors, FLAT antagonists, TRPA1 modulators, voltage-gated sodium channel binder, cannabinoid receptor-2 agonists, sigma-1 receptor antagonists, etc. Sigma-1 receptor is a distinct type of opioid receptor and several patents were obtained for sigma-1 receptor antagonists for the treatment of neuropathic pain. These molecules were found to have a profound role in the management of neuropathic pain. The present review describes the validated therapeutic targets, potential chemical scaffolds, and crucial protein-ligand interactions for the management of neuropathic pain based on the recently reported computational methodologies of the present and past decades. The study can help the researcher to discover newer drugs/drug-like molecules against neuropathic pain.
    Matched MeSH terms: Ligands
  11. Fulltext Advances in Aptamer-Based Biosensors and Cell-Internalizing SELEX Technology for Diagnostic and Therapeutic Application
    Gan Z, Roslan MAM, Abd Shukor MY, Halim M, Yasid NA, Abdullah J, et al.
    Biosensors (Basel), 2022 Oct 25;12(11).
    PMID: 36354431 DOI: 10.3390/bios12110922
    Aptamers are a group of synthetic single-stranded nucleic acids. They are generated from a random library of single-stranded DNA or RNA by a technology named systematic evolution of ligands by exponential enrichment (SELEX). SELEX is a repetitive process to select and identify suitable aptamers that show high affinity and specificity towards target cells. Great strides have been achieved in the design, construction, and use of aptamers up to this point. However, only a small number of aptamer-based applications have achieved widespread commercial and clinical acceptance. Additionally, finding more effective ways to acquire aptamers with high affinity remains a challenge. Therefore, it is crucial to thoroughly examine the existing dearth and advancement in aptamer-related technologies. This review focuses on aptamers that are generated by SELEX to detect pathogenic microorganisms and mammalian cells, as well as in cell-internalizing SELEX for diagnostic and therapeutic purposes. The development of novel aptamer-based biosensors using optical and electrical methods for microbial detection is reported. The applications and limitations of aptamers are also discussed.
    Matched MeSH terms: Ligands
  12. Fulltext Binding Affinity of a Highly Sensitive Au/Ag/Au/Chitosan-Graphene Oxide Sensor Based on Direct Detection of Pb2+and Hg2+Ions
    Kamaruddin NH, Bakar AAA, Mobarak NN, Zan MSD, Arsad N
    Sensors (Basel), 2017 Oct 06;17(10).
    PMID: 28984826 DOI: 10.3390/s17102277
    The study of binding affinity is essential in surface plasmon resonance (SPR) sensing because it allows researchers to quantify the affinity between the analyte and immobilised ligands of an SPR sensor. In this study, we demonstrate the derivation of the binding affinity constant, K, for Pb2+and Hg2+ions according to their SPR response using a gold/silver/gold/chitosan-graphene oxide (Au/Ag/Au/CS-GO) sensor for the concentration range of 0.1-5 ppm. The higher affinity of Pb2+to binding with the CS-GO sensor explains the outstanding sensitivity of 2.05 °ppm-1against 1.66 °ppm-1of Hg2+. The maximum signal-to-noise ratio (SNR) upon detection of Pb2+is 1.53, and exceeds the suggested logical criterion of an SNR. The Au/Ag/Au/CS-GO SPR sensor also exhibits excellent repeatability in Pb2+due to the strong bond between its functional groups and this cation. The adsorption data of Pb2+and Hg2+on the CS-GO sensor fits well with the Langmuir isotherm model where the affinity constant, K, of Pb2+and Hg2+ions is computed. The affinity of Pb2+ions to the Au/Ag/Au/CS-GO sensor is significantly higher than that of Hg2+based on the value of K, 7 × 10⁵ M-1and 4 × 10⁵ M-1, respectively. The higher shift in SPR angles due to Pb2+and Hg2+compared to Cr3+, Cu2+and Zn2+ions also reveals the greater affinity of the CS-GO SPR sensor to them, thus supporting the rationale for obtaining K for these two heavy metals. This study provides a better understanding on the sensing performance of such sensors in detecting heavy metal ions.
    Matched MeSH terms: Ligands
  13. Recent advances in galactose-engineered nanocarriers for the site-specific delivery of siRNA and anticancer drugs
    Jain A, Jain A, Parajuli P, Mishra V, Ghoshal G, Singh B, et al.
    Drug Discov Today, 2018 05;23(5):960-973.
    PMID: 29129804 DOI: 10.1016/j.drudis.2017.11.003
    Galactosylated nanocarriers have recently emerged as viable and versatile tools to deliver drugs at an optimal rate specifically to their target tissues or cells, thus maximizing their therapeutic benefits while circumventing off-target effects. The abundance of lectin receptors on cell surfaces makes the galactosylated carriers suitable for the targeted delivery of bioactives. Additionally, tethering of galactose (GAL) to various carriers, including micelles, liposomes, and nanoparticles (NPs), might also be appropriate for drug delivery. Here, we review recent advances in the development of galactosylated nanocarriers for active tumor targeting. We also provide a brief overview of the targeting mechanisms and cell receptor theory involved in the ligand-receptor-mediated delivery of drug carriers.
    Matched MeSH terms: Ligands
  14. GPCRs through the keyhole: the role of protein flexibility in ligand binding to β-adrenoceptors
    Emtage AL, Mistry SN, Fischer PM, Kellam B, Laughton CA
    J Biomol Struct Dyn, 2016 Aug 17.
    PMID: 27532213
    G protein-coupled receptors (GPCRs) are proteins of pharmaceutical importance, with over 30% of all drugs in clinical use targeting them. Increasing numbers of X-ray crystal (XRC) structures of GPCRs offer a wealth of data relating to ligand binding. For the β-adrenoceptors (β-ARs), XRC structures are available for human β2- and turkey β1-subtypes, in complexes with a range of ligands. While these structures provide insight into the origins of ligand structure-activity relationships (SARs), questions remain. The ligands in all published complexed XRC structures lack extensive substitution, with no obvious way the ligand-binding site can accommodate β1-AR-selective antagonists with extended side-chains para- to the common aryloxypropanolamine pharmacophore. Using standard computational docking tools with such ligands generally returns poses that fail to explain known SARs. Application of our Active Site Pressurization (ASP) modelling method to β-AR XRC structures and homology models however, reveals a dynamic area in the ligand-binding pocket that, through minor changes in amino acid side chain orientations, opens a fissure between transmembrane (TM) helices H4 and H5, exposing intra-membrane space. This fissure, which we term the 'keyhole', is ideally located to accommodate extended moieties present in many high-affinity β1-AR-selective ligands; allowing the rest of the ligand structure to adopt a canonical pose in the orthosteric binding site. We propose the keyhole may be a feature of both β1- and β2-ARs, but that subtle structural differences exist between the two, contributing to subtype-selectivity. This has consequences for the rational design of future generations of subtype-selective ligands for these therapeutically important targets.
    Matched MeSH terms: Ligands
  15. Role of P34S, G169R, R296C, and S486T Substitutions in Ligand Access and Catalysis for Cytochrome P450 2D6 Allelic Variants CYP2D6*14A and CYP2D6*14B
    Dong AN, Ahemad N, Pan Y, Palanisamy UD, Yiap BC, Ong CE
    Drug Metab Bioanal Lett, 2022;15(1):51-63.
    PMID: 35049443 DOI: 10.2174/1872312815666220113125232
    BACKGROUND: Genetic polymorphism of cytochrome P450 (CYP) contributes to variability in drug metabolism, clearance, and response. This study aimed to investigate the functional and molecular basis for altered ligand binding and catalysis in CYP2D6*14A and CYP2D6*14B, two unique alleles common in the Asian population.

    METHODS: CYP proteins expressed in Escherichia coli were studied using the substrate 3-cyano-7- ethoxycoumarin (CEC) and inhibitor probes (quinidine, fluoxetine, paroxetine, terbinafine) in the enzyme assay. Computer modelling was additionally used to create three-dimensional structures of the CYP2D6*14 variants.

    RESULTS: Kinetics data indicated significantly reduced intrinsic clearance in CYP2D6*14 variants, suggesting that P34S, G169R, R296C, and S486T substitutions worked cooperatively to alter the conformation of the active site that negatively impacted the deethylase activity of CYP2D6. For the inhibition studies, IC50 values decreased in quinidine, paroxetine, and terbinafine but increased in fluoxetine, suggesting a varied ligand-specific susceptibility to inhibition. Molecular docking further demonstrated the role of P34S and R296C in altering access channel dimensions, thereby affecting ligand access and binding and subsequently resulting in varied inhibition potencies.

    CONCLUSION: In summary, the differential selectivity of CYP2D6*14 variants for the ligands (substrate and inhibitor) was governed by the alteration of the active site and access channel architecture induced by the natural mutations found in the alleles.

    Matched MeSH terms: Ligands
  16. Machine learning and molecular simulation ascertain antimicrobial peptide against Klebsiella pneumoniae from public database
    Al-Khdhairawi A, Sanuri D, Akbar R, Lam SD, Sugumar S, Ibrahim N, et al.
    Comput Biol Chem, 2023 Feb;102:107800.
    PMID: 36516617 DOI: 10.1016/j.compbiolchem.2022.107800
    Antimicrobial peptides (AMPs) are short peptides with a broad spectrum of antimicrobial activity. They play a key role in the host innate immunity of many organisms. The growing threat of microorganisms resistant to antimicrobial agents and the lack of new commercially available antibiotics have made in silico discovery of AMPs increasingly important. Machine learning (ML) has improved the speed and efficiency of AMP discovery while reducing the cost of experimental approaches. Despite various ML platforms developed, there is still a lack of integrative use of ML platforms for AMP discovery from publicly available protein databases. Therefore, our study aims to screen potential AMPs with antibiofilm properties from databases using ML platforms, followed by protein-peptide molecular docking analysis and molecular dynamics (MD) simulations. A total of 5850 peptides classified as non-AMP were screened from UniProtKB and analyzed using various online ML platforms (e.g., CAMPr3, DBAASP, dPABBs, Hemopred, and ToxinPred). Eight potential AMP peptides against Klebsiella pneumoniae with antibiofilm, non-toxic and non-hemolytic properties were then docked to MrkH, a transcriptional regulator of type 3 fimbriae involved in biofilm formation. Five of eight peptides bound more strongly than the native MrkH ligand when analyzed using HADDOCK and HPEPDOCK. Following the docking studies, our MD simulated that a Neuropeptide B (Peptide 3) bind strongly to the MrkH active sites. The discovery of putative AMPs that exceed the binding energies of the native ligand underscores the utility of the combined ML and molecular simulation strategies for discovering novel AMPs with antibiofilm properties.
    Matched MeSH terms: Ligands
  17. On-Demand Ligand-Base DNA Sensor with Electrochemical Impedance Spectroscopy
    Han H, Sabani NB, Nobusawa K, Takei F, Nakatani K, Yamashita I
    Anal Chem, 2023 Jul 04;95(26):9729-9733.
    PMID: 37341999 DOI: 10.1021/acs.analchem.3c01126
    We have developed a DNA sensor that can be finalized to detect a specific target on demand. The electrode surface was modified with 2,7-diamino-1,8-naphthyridine (DANP), a small molecule with nanomolar affinity for the cytosine bulge structure. The electrode was immersed in a solution of synthetic probe-DNA that had a cytosine bulge structure at one end and a complementary sequence to the target DNA at the other end. The strong binding between the cytosine bulge and DANP anchored the probe DNAs to the electrode surface, and the electrode became ready for target DNA sensing. The complementary sequence portion of the probe DNA can be changed as requested, allowing for the detection of a wide variety of targets. Electrochemical impedance spectroscopy (EIS) with the modified electrode detected target DNAs with a high sensitivity. The charge transfer resistance (Rct) extracted from EIS showed a logarithmic relationship with the concentration of target DNA. The limit of detection (LoD) was less than 0.01 μM. By this method, highly sensitive DNA sensors for various target sequences could be easily produced.
    Matched MeSH terms: Ligands
  18. Fulltext Contemporary Approaches to the Discovery and Development of Broad-Spectrum Natural Product Prototypes for the Control of Coronaviruses
    Hanna GS, Choo YM, Harbit R, Paeth H, Wilde S, Mackle J, et al.
    J Nat Prod, 2021 Nov 26;84(11):3001-3007.
    PMID: 34677966 DOI: 10.1021/acs.jnatprod.1c00625
    The pressing need for SARS-CoV-2 controls has led to a reassessment of strategies to identify and develop natural product inhibitors of zoonotic, highly virulent, and rapidly emerging viruses. This review article addresses how contemporary approaches involving computational chemistry, natural product (NP) and protein databases, and mass spectrometry (MS) derived target-ligand interaction analysis can be utilized to expedite the interrogation of NP structures while minimizing the time and expense of extraction, purification, and screening in BioSafety Laboratories (BSL)3 laboratories. The unparalleled structural diversity and complexity of NPs is an extraordinary resource for the discovery and development of broad-spectrum inhibitors of viral genera, including Betacoronavirus, which contains MERS, SARS, SARS-CoV-2, and the common cold. There are two key technological advances that have created unique opportunities for the identification of NP prototypes with greater efficiency: (1) the application of structural databases for NPs and target proteins and (2) the application of modern MS techniques to assess protein-ligand interactions directly from NP extracts. These approaches, developed over years, now allow for the identification and isolation of unique antiviral ligands without the immediate need for BSL3 facilities. Overall, the goal is to improve the success rate of NP-based screening by focusing resources on source materials with a higher likelihood of success, while simultaneously providing opportunities for the discovery of novel ligands to selectively target proteins involved in viral infection.
    Matched MeSH terms: Ligands
  19. Pharmacophore Based Virtual Screening Approach to Identify Selective PDE4B Inhibitors
    Gaurav A, Gautam V
    Iran J Pharm Res, 2017;16(3):910-923.
    PMID: 29201082
    Phosphodiesterase 4 (PDE4) has been established as a promising target in asthma and chronic obstructive pulmonary disease. PDE4B subtype selective inhibitors are known to reduce the dose limiting adverse effect associated with non-selective PDE4B inhibitors. This makes the development of PDE4B subtype selective inhibitors a desirable research goal. To achieve this goal, ligand based pharmacophore modeling approach is employed. Separate pharmacophore hypotheses for PDE4B and PDE4D inhibitors were generated using HypoGen algorithm and 106 PDE4 inhibitors from literature having thiopyrano [3,2-d] Pyrimidines, 2-arylpyrimidines, and triazines skeleton. Suitable training and test sets were created using the molecules as per the guidelines available for HypoGen program. Training set was used for hypothesis development while test set was used for validation purpose. Fisher validation was also used to test the significance of the developed hypothesis. The validated pharmacophore hypotheses for PDE4B and PDE4D inhibitors were used in sequential virtual screening of zinc database of drug like molecules to identify selective PDE4B inhibitors. The hits were screened for their estimated activity and fit value. The top hit was subjected to docking into the active sites of PDE4B and PDE4D to confirm its selectivity for PDE4B. The hits are proposed to be evaluated further using in-vitro assays.
    Matched MeSH terms: Ligands
  20. Fulltext Novel Complex of Zinc (II) Dichloroethylenediamine: Synthesis, Characterization, In-silico, and In-vitro Evaluation against Cervical Cancer Cells
    Raya I, Kartina D, Wijaya RI, Irfandi R, Abdalrazaq EA, Prihantono P, et al.
    Asian Pac J Cancer Prev, 2023 Dec 01;24(12):4155-4165.
    PMID: 38156851 DOI: 10.31557/APJCP.2023.24.12.4155
    OBJECTIVE: Cervical cancer is a malignancy originating from the cervix and often caused by oncogenic Human Papilloma Virus (HPV), specifically subtypes 16 and 18. Anticancer drugs are chemotherapeutic compounds used for cancer treatment. Therefore, this research aims to synthesize and characterize Zinc (II) dichloroethylenediamine (Zn(en)Cl2) complex, as well as determine its antiproliferative activity against HeLa cells. The Zn(en)Cl2 complex was successfully synthesized, and the antiproliferative activity was tested.

    METHODS: The synthesis involved reacting ethylenediamine and KCl with Zn metal. The complex formed was characterized using a conductometer, UV-Vis spectroscopy, FT-IR spectroscopy, and XRD, while the activity was measured against HeLa cells.

    RESULT: The synthesis yielded a 56.12% conversion with a melting point of 198-200 oC and a conductivity value of 2.02 mS/cm. The Zn(en)Cl2 complex showed potential activity against HeLa cells with an IC50 value of 898.35 µg/mL, which was evidenced by changes in the morphological structure of HeLa cells. Its interaction with DNA targets was investigated by employing molecular docking.

    CONCLUSION: The observed data indicated that the Zn(en)Cl2 complex bound to DNA at the nitrogenous base Guanine (DG) by coordinate covalent bonds. Interestingly, DG maintained interaction with the complex until the end of the docking simulation. Additionally, molecular dynamics (MD) simulation was conducted, and the results showed that Zn(en)Cl2 remained bound to the DNA binding pocket all through the process.

    Matched MeSH terms: Ligands
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