10 results on '"Chalmers, DK"'
Search Results
2. Cyclosporin Structure and Permeability: From A to Z and Beyond.
- Author
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Corbett KM, Ford L, Warren DB, Pouton CW, and Chalmers DK
- Subjects
- Animals, Cyclosporins chemistry, Humans, Models, Chemical, Protein Conformation, Cell Membrane metabolism, Cell Membrane Permeability, Cyclosporins metabolism
- Abstract
Cyclosporins are natural or synthetic undecapeptides with a wide range of actual and potential pharmaceutical applications. Several members of the cyclosporin compound family have remarkably high passive membrane permeabilities that are not well-described by simple structural metrics. Here we review experimental studies of cyclosporin structure and permeability, including cyclosporin-metal complexes. We also discuss models for the conformation-dependent permeability of cyclosporins and similar compounds. Finally, we identify current knowledge gaps in the literature and provide recommendations regarding future avenues of exploration.
- Published
- 2021
- Full Text
- View/download PDF
3. Free Energy Methods in Drug Design: Prospects of "Alchemical Perturbation" in Medicinal Chemistry.
- Author
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Williams-Noonan BJ, Yuriev E, and Chalmers DK
- Subjects
- Humans, Thermodynamics, Chemistry, Pharmaceutical methods, Drug Design
- Abstract
Underpinning all drug discovery projects is the interaction between a drug and its target, usually a protein. Thus, improved methods for predicting the magnitude of protein-ligand interactions have the potential to improve the efficiency of drug development. In this review, we describe the principles of free energy methods used for the calculation of protein-ligand binding free energies, the challenges associated with these methods, and recent advances developed to address these difficulties. We then present case studies from 2005 to 2017, each demonstrating that alchemical free energy methods can assist rational drug design projects. We conclude that alchemical methods are becoming a feasible reality in medicinal chemistry research due to improved computational resources and algorithms and that alchemical free energy predictions methods are close to becoming a mainstream tool for medicinal chemists.
- Published
- 2018
- Full Text
- View/download PDF
4. Design, Synthesis, and Characterization of Cyclic Peptidomimetics of the Inducible Nitric Oxide Synthase Binding Epitope That Disrupt the Protein-Protein Interaction Involving SPRY Domain-Containing Suppressor of Cytokine Signaling Box Protein (SPSB) 2 and Inducible Nitric Oxide Synthase.
- Author
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Harjani JR, Yap BK, Leung EW, Lucke A, Nicholson SE, Scanlon MJ, Chalmers DK, Thompson PE, Norton RS, and Baell JB
- Subjects
- Animals, Binding Sites drug effects, Macrophages drug effects, Macrophages metabolism, Mice, Models, Molecular, Molecular Conformation, Molecular Dynamics Simulation, Nitric Oxide Synthase Type II metabolism, Peptides chemical synthesis, Peptides chemistry, Peptidomimetics chemical synthesis, Peptidomimetics chemistry, Protein Binding drug effects, Suppressor of Cytokine Signaling Proteins metabolism, B30.2-SPRY Domain drug effects, Drug Design, Nitric Oxide Synthase Type II antagonists & inhibitors, Peptides pharmacology, Peptidomimetics pharmacology, Suppressor of Cytokine Signaling Proteins antagonists & inhibitors
- Abstract
SPRY domain-containing suppressor of cytokine signaling box protein (SPSB) 2-deficient macrophages have been found to exhibit prolonged expression of inducible nitric oxide synthase (iNOS) and enhanced killing of persistent pathogens, suggesting that inhibitors of the SPSB2-iNOS interaction have potential as novel anti-infectives. In this study, we describe the design, synthesis, and characterization of cyclic peptidomimetic inhibitors of the SPSB2-iNOS interaction constrained by organic linkers to improve stability and druggability. SPR, ITC, and (19)F NMR analyses revealed that the most potent cyclic peptidomimetic bound to the iNOS binding site of SPSB2 with low nanomolar affinity (KD 29 nM), a 10-fold improvement over that of the linear peptide DINNN (KD 318 nM), and showed strong inhibition of SPSB2-iNOS interaction in macrophage cell lysates. This study exemplifies a novel approach to cyclize a Type II β-turn linear peptide and provides a foundation for future development of this group of inhibitors as new anti-infectives.
- Published
- 2016
- Full Text
- View/download PDF
5. A potent cyclic peptide targeting SPSB2 protein as a potential anti-infective agent.
- Author
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Yap BK, Leung EW, Yagi H, Galea CA, Chhabra S, Chalmers DK, Nicholson SE, Thompson PE, and Norton RS
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- Animals, Binding Sites, Humans, Immunity, Innate drug effects, Macrophages drug effects, Macrophages metabolism, Magnetic Resonance Spectroscopy, Mice, Molecular Targeted Therapy, Peptides, Cyclic blood, Peptides, Cyclic metabolism, Protein Conformation, Protein Stability, Protein Transport, Suppressor of Cytokine Signaling Proteins chemistry, Surface Plasmon Resonance, Anti-Infective Agents chemistry, Anti-Infective Agents pharmacology, Nitric Oxide Synthase Type II metabolism, Peptides, Cyclic chemistry, Peptides, Cyclic pharmacology, Suppressor of Cytokine Signaling Proteins metabolism
- Abstract
The protein SPSB2 mediates proteosomal degradation of inducible nitric oxide synthase (iNOS). Inhibitors of SPSB2-iNOS interaction may prolong the lifetime of iNOS and thereby enhance the killing of persistent pathogens. We have designed a cyclic peptide, Ac-c[CVDINNNC]-NH2, containing the key sequence motif mediating the SPSB2-iNOS interaction, which binds to the iNOS binding site on SPSB2 with a Kd of 4.4 nM, as shown by SPR, [(1)H,(15)N]-HSQC, and (19)F NMR. An in vitro assay on macrophage cell lysates showed complete inhibition of SPSB2-iNOS interactions by the cyclic peptide. Furthermore, its solution structure closely matched (backbone rmsd 1.21 Å) that of the SPSB2-bound linear DINNN peptide. The designed peptide was resistant to degradation by the proteases pepsin, trypsin, and chymotrypsin and stable in human plasma. This cyclic peptide exemplifies potentially a new class of anti-infective agents that acts on the host innate response, thereby avoiding the development of pathogen resistance.
- Published
- 2014
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6. Discovery of 7-hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[b]furan (BNC105), a tubulin polymerization inhibitor with potent antiproliferative and tumor vascular disrupting properties.
- Author
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Flynn BL, Gill GS, Grobelny DW, Chaplin JH, Paul D, Leske AF, Lavranos TC, Chalmers DK, Charman SA, Kostewicz E, Shackleford DM, Morizzi J, Hamel E, Jung MK, and Kremmidiotis G
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- Anisoles chemical synthesis, Anisoles chemistry, Aorta cytology, Benzofurans chemical synthesis, Benzofurans chemistry, Cells, Cultured, Endothelium, Vascular cytology, Humans, Structure-Activity Relationship, Tubulin Modulators chemical synthesis, Tubulin Modulators chemistry, Anisoles pharmacology, Aorta drug effects, Benzofurans pharmacology, Cell Proliferation drug effects, Endothelium, Vascular drug effects, Neovascularization, Physiologic drug effects, Tubulin Modulators pharmacology
- Abstract
A structure-activity relationship (SAR) guided design of novel tubulin polymerization inhibitors has resulted in a series of benzo[b]furans with exceptional potency toward cancer cells and activated endothelial cells. The potency of early lead compounds has been substantially improved through the synergistic effect of introducing a conformational bias and additional hydrogen bond donor to the pharmacophore. Screening of a focused library of potent tubulin polymerization inhibitors for selectivity against cancer cells and activated endothelial cells over quiescent endothelial cells has afforded 7-hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[b]furan (BNC105, 8) as a potent and selective antiproliferative. Because of poor solubility, 8 is administered as its disodium phosphate ester prodrug 9 (BNC105P), which is rapidly cleaved in vivo to return the active 8. 9 exhibits both superior vascular disrupting and tumor growth inhibitory properties compared with the benchmark agent combretastatin A-4 disodium phosphate 5 (CA4P).
- Published
- 2011
- Full Text
- View/download PDF
7. Probing the fibrate binding specificity of rat liver fatty acid binding protein.
- Author
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Chuang S, Velkov T, Horne J, Wielens J, Chalmers DK, Porter CJ, and Scanlon MJ
- Subjects
- Animals, Binding Sites, Carboxylic Acids chemistry, Clofibric Acid chemistry, Clofibric Acid pharmacology, Esters chemistry, Fatty Acid-Binding Proteins chemistry, Fenofibrate analogs & derivatives, Fenofibrate chemistry, Fenofibrate metabolism, Hypolipidemic Agents chemistry, Hypolipidemic Agents pharmacology, Ligands, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Conformation, Rats, Spectrometry, Fluorescence, Substrate Specificity, Temperature, Thermodynamics, Clofibric Acid metabolism, Fatty Acid-Binding Proteins metabolism, Hypolipidemic Agents metabolism, Liver metabolism
- Abstract
Liver-fatty acid binding protein (L-FABP) is found in high levels in enterocytes and is involved in cytosolic solubilization of fatty acids. In addition, L-FABP has been shown to bind endogenous and exogenous lipophilic compounds, suggesting that it may also play a role in modulating their absorption and disposition within enterocytes. Previously, we have described binding of L-FABP to a range of drugs, including a series of fibrates. In the present study, we have generated structural models of L-FABP-fibrate complexes and undertaken thermodynamic analysis of the binding of fibrates containing either a carboxylic acid or ester functionality. Analysis of the current data reveals that both the location and the energetics of binding are different for fibrates that contain a carboxylate compared to those that do not. As such, the data presented in this study suggest potential mechanisms that underpin molecular recognition and dictate specificity in the interaction between fibrates and L-FABP.
- Published
- 2009
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8. 2-aminothienopyridazines as novel adenosine A1 receptor allosteric modulators and antagonists.
- Author
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Ferguson GN, Valant C, Horne J, Figler H, Flynn BL, Linden J, Chalmers DK, Sexton PM, Christopoulos A, and Scammells PJ
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- Allosteric Regulation drug effects, Allosteric Site drug effects, Dose-Response Relationship, Drug, Humans, Kinetics, Molecular Structure, Pyridazines chemical synthesis, Pyridazines chemistry, Receptor, Adenosine A1 chemistry, Small Molecule Libraries, Stereoisomerism, Structure-Activity Relationship, Thiophenes chemical synthesis, Thiophenes chemistry, Adenosine A1 Receptor Agonists, Adenosine A1 Receptor Antagonists, Pyridazines pharmacology, Thiophenes pharmacology
- Abstract
A pharmacophore-based screen identified 32 compounds including ethyl 5-amino-3-(4- tert-butylphenyl)-4-oxo-3,4-dihydrothieno[3,4- d]pyridazine-1-carboxylate ( 8) as a new allosteric modulator of the adenosine A1 receptor (A1AR). On the basis of this lead, various derivatives were prepared and evaluated for activity at the human A 1AR. A number of the test compounds allosterically stabilized agonist-receptor-G protein ternary complexes in dissociation kinetic assays, but were found to be more potent as antagonists in subsequent functional assays of ERK1/2 phosphorylation. Additional experiments on the most potent antagonist, 13b, investigating A1AR-mediated [(35)S]GTPgammaS binding and [(3)H]CCPA equilibrium binding confirmed its antagonistic mode of action and also identified inverse agonism. This study has thus identified a new class of A1AR antagonists that can also recognize the receptor's allosteric site with lower potency.
- Published
- 2008
- Full Text
- View/download PDF
9. An orally bioavailable oxime ether capsid binder with potent activity against human rhinovirus.
- Author
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Watson KG, Brown RN, Cameron R, Chalmers DK, Hamilton S, Jin B, Krippner GY, Luttick A, McConnell DB, Reece PA, Ryan J, Stanislawski PC, Tucker SP, Wu WY, Barnard DL, and Sidwell RW
- Subjects
- Administration, Oral, Animals, Antiviral Agents pharmacokinetics, Antiviral Agents pharmacology, Biological Availability, Cell Line, Ethers, Female, Humans, Male, Mice, Oximes pharmacokinetics, Oximes pharmacology, Piperidines pharmacokinetics, Piperidines pharmacology, Protein Binding, Pyridazines pharmacokinetics, Pyridazines pharmacology, Rats, Structure-Activity Relationship, Antiviral Agents chemical synthesis, Capsid metabolism, Oximes chemical synthesis, Rhinovirus drug effects
- Abstract
A series of capsid-binding compounds was screened against human rhinovirus (HRV) using a CPE based assay. The ethyl oxime ether 14 was found to have outstanding anti-HRV activity (median IC(50) 4.75 ng/mL), and unlike the equivalent ethyl ester compound 3 (Pirodavir), it has good oral bioavailability, making it a promising development candidate. Compound 14 illustrates that an oxime ether group can act as a metabolically stable bioisostere for an ester functionality.
- Published
- 2003
- Full Text
- View/download PDF
10. Thyroid hormone uptake by hepatocytes: structure-activity relationships of phenylanthranilic acids with inhibitory activity.
- Author
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Chalmers DK, Scholz GH, Topliss DJ, Kolliniatis E, Munro SL, Craik DJ, Iskander MN, and Stockigt JR
- Subjects
- Animals, Chemical Phenomena, Chemistry, Physical, Flufenamic Acid pharmacology, Liver drug effects, Liver Neoplasms, Experimental, Meclofenamic Acid pharmacology, Mefenamic Acid pharmacology, Molecular Structure, Rats, Structure-Activity Relationship, Tumor Cells, Cultured, ortho-Aminobenzoates pharmacology, Liver metabolism, Triiodothyronine metabolism, ortho-Aminobenzoates chemistry
- Abstract
The synthesis of a series of mono- and disubstituted N-phenylanthranilic acids is described. Substituents on the phenyl ring include Cl, CN, OH, CF3, Br, I, CH3, OCH3, and OCF2CF2H. These compounds have been tested for their inhibitory effect on triiodothyronine (T3) uptake by H4 hepatocytes. The nonsteroidal antiinflammatory drugs flufenamic acid, mefenamic acid, and meclofenamic acid and the structurally related compounds 2,3-dimethyldiphenylamine and diclofenac were also tested. The most potent compounds were found to be, in order of decreasing activity, meclofenamic acid (2,6-Cl2,3-CH3), flufenamic acid (3-CF3), mefenamic acid (2,3-(CH3)2), and the compounds with 3,5-Cl2 and 3-OCF2CF2H substituents. The least potent compounds had 3-CN and 3-OH substituents. An analysis of quantitative structure-activity relationships (QSAR) for the series of phenylanthranilic acids showed that the inhibition of T3 uptake is highly dependent on the hydrophobicity of the compound. The relationship between uptake inhibition and the calculated octanol-water partition coefficient (clogP) was found to be parabolic, with optimum inhibitory activity found when the clogP of the phenylanthranilic acid was 5.7. It was also found that the 1-carboxylic acid group of the phenylanthranilic acids was not a prerequisite for uptake inhibition to occur, but its removal or alteration resulted in reduced inhibition.
- Published
- 1993
- Full Text
- View/download PDF
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