| 1. |
- Orrling, Kristina M., et al.
(författare)
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α-Substituted Norstatines as the Transistion-State Mimic in Inhibitors of Multiple Digestive Vacuole Malaria Aspartic Proteases
- 2009
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 17:16, s. 5933-5949
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Tidskriftsartikel (refereegranskat)abstract
- The impact of moving the P1 side-chain from the β-position to the α-position in norstatine-containing plasmepsin inhibitors was investigated, generating two new classes of tertiary alcohol-comprising α-benzylnorstatines and α-phenylnorstatines. Twelve α-substituted norstatines were designed, synthesized and evaluated for their inhibitory potencies against plasmepsin II and the plasmepsin IV orthologues (PM4) present in the digestive vacuole of all four Plasmodium species causing malaria in man. New synthetic routes were developed for producing the desired α-substituted norstatines as pure stereoisomers. The best compounds provided Ki values in the nanomolar range for all PM4, with a best value of 110 nm in PM4 from P. ovale. In addition, excellent selectivity over the closely related human aspartic protease Cathepsin D was achieved. The loss of affinity to P. falciparum PM4, which was experienced upon the move of the P1 substituent, was rationalized by the calculation of inhibitor–protein binding affinities using the linear interaction energy method (LIE).
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| 2. |
- Almlöf, Martin, et al.
(författare)
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Molecular dynamics study of heparin based coatings
- 2008
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Ingår i: Biomaterials. - : Elsevier BV. - 0142-9612 .- 1878-5905. ; 29:33, s. 4463-4469
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Tidskriftsartikel (refereegranskat)abstract
- Heparin based surface coatings can be used to improve the biocompatibility of metallic surfaces such as vascular stents. Here, we report molecular dynamics simulations of a macromolecular conjugate of heparin used to prepare such surfaces. The structural properties of the heparin conjugate are investigated for different degrees of hydration, to allow comparison with spectroscopic results. The simulations show that the polymer becomes more compact with an increasing degree of inter-chain interactions as the hydration increases. This is also accompanied by changes in the interaction patterns among the heparin chains, where counter ions become looser associated with the disaccharide units and their strong interactions can be partly replaced by water molecules and heparin hydroxyl groups. The structural information that can be obtained from computer simulations of this type of coatings can be very valuable for understanding and further development of functional interfaces, since very little is known experimentally regarding their detailed structural properties. (C) 2008 Elsevier Ltd. All rights reserved.
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| 3. |
- Bjelic, Sinisa, et al.
(författare)
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Computational inhibitor design against malaria plasmepsins
- 2007
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Ingår i: Cellular and Molecular Life Sciences (CMLS). - : Springer Science and Business Media LLC. - 1420-682X .- 1420-9071. ; 64:17, s. 2285-2305
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Tidskriftsartikel (refereegranskat)abstract
- Plasmepsins are aspartic proteases involved in the degradation of the host cell hemoglobin that is used as a food source by the malaria parasite. Plasmepsins are highly promising as drug targets, especially when combined with the inhibition of falcipains that are also involved in hemoglobin catabolism. In this review, we discuss the mechanism of plasmepsins I-IV in view of the interest in transition state mimetics as potential compounds for lead development. Inhibitor development against plasmepsin II as well as relevant crystal structures are summarized in order to give an overview of the field. Application of computational techniques, especially binding affinity prediction by the linear interaction energy method, in the development of malarial plasmepsin inhibitors has been highly successful and is discussed in detail. Homology modeling and molecular docking have been useful in the current inhibitor design project, and the combination of such methods with binding free energy calculations is analyzed.
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| 4. |
- Brandsdal, B., Österberg, F., Almlöf, M., Feierberg, I., Luzhkov, V.B., et al.
(författare)
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Free Energy Calculations and Ligand Binding
- 2003
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Ingår i: Adv. Prot. Chem.. ; 66, s. 123-
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Tidskriftsartikel (refereegranskat)
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| 5. |
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| 6. |
- Fransson, Emil, 1986, et al.
(författare)
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A fast neural network surrogate model for the eigenvalues of QuaLiKiz
- 2023
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Ingår i: Physics of Plasmas. - 1089-7674 .- 1070-664X. ; 30:12
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Tidskriftsartikel (refereegranskat)abstract
- We introduce a neural network surrogate model that predicts the eigenvalues for the turbulent microinstabilities, based on the gyrokinetic eigenvalue solver in QuaLiKiz. The model quickly provides information about the dominant instability for specific plasma conditions, and in addition, the eigenvalues offer a pathway for extrapolating transport fluxes. The model is trained on a 5 × 106 data points large dataset based on experimental data from discharges at the joint European torus, where each data point represents a QuaLiKiz simulation. The most accurate model was obtained when the task was split into a classification task to decide if the imaginary part of eigenvalues were stable ( ≤ 0 ) or not, and a regression model to calculate the eigenvalues once the classifier predicted the unstable class.
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| 7. |
- Graffner-Nordberg, Malin, et al.
(författare)
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Design, Synthesis, Computational Prediction and Biological Evaluation of Ester Soft Drugs as Inhibitors of Dihydrofolate Reductase from Pneumocystis Carinii
- 2001
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 44:15, s. 2391-2402
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Tidskriftsartikel (refereegranskat)abstract
- A series of lipophilic soft drugs structurally related to the nonclassical dihydrofolate reductase (DHFR) inhibitors trimetrexate and piritrexim have been designed, synthesized, and evaluated in DHFR assays, with special emphasis on the inhibition of P. carinii DHFR. The best inhibitors, encompassing an ester bond in the bridge connecting the two aromatic systems, were approximately 10 times less potent than trimetrexate and piritrexim. The metabolites were designed to be poor inhibitors. Furthermore, molecular dynamics simulations of three ligands in complex with DHFR from Pneumocystis carinii and from the human enzyme were conducted in order to better understand the factors determining the selectivity. A correct ranking of the relative inhibition of DHFR was achieved utilizing the linear interaction energy method. The soft drugs are intended for local administration. One representative ester was selected for a pharmacokinetic study in rats where it was found to undergo fast metabolic degradation to the predicted inactive metabolites.
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| 8. |
- Guo, Xiaohu, et al.
(författare)
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Structure and mechanism of a phage-encoded SAM lyase revises catalytic function of enzyme family
- 2021
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Ingår i: eLIFE. - : eLife Sciences Publications Ltd. - 2050-084X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- The first S-adenosyl methionine (SAM) degrading enzyme (SAMase) was discovered in bacteriophage T3, as a counter-defense against the bacterial restriction-modification system, and annotated as a SAM hydrolase forming 5’-methyl-thioadenosine (MTA) and L-homoserine. From environmental phages, we recently discovered three SAMases with barely detectable sequence similarity to T3 SAMase and without homology to proteins of known structure. Here, we present the very first phage SAMase structures, in complex with a substrate analogue and the product MTA. The structure shows a trimer of alpha–beta sandwiches similar to the GlnB-like superfamily, with active sites formed at the trimer interfaces. Quantum-mechanical calculations, thin-layer chromatography, and nuclear magnetic resonance spectroscopy demonstrate that this family of enzymes are not hydrolases but lyases forming MTA and L-homoserine lactone in a unimolecular reaction mechanism. Sequence analysis and in vitro and in vivo mutagenesis support that T3 SAMase belongs to the same structural family and utilizes the same reaction mechanism.
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| 9. |
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| 10. |
- Gutiérrez-de-Terán, Hugo, et al.
(författare)
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Computational analysis of plasmepsin IV bound to an allophenylnorstatine inhibitor
- 2006
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Ingår i: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 580:25, s. 5910-5916
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Tidskriftsartikel (refereegranskat)abstract
- The plasmepsin proteases from the malaria parasite Plasmodium falciparum are attracting attention as putative drug targets. A recently published crystal structure of Plasmodium malariae plasmepsin IV bound to an allophenylnorstatine inhibitor [Clemente, J.C. et al. (2006) Acta Crystallogr. D 62, 246252] provides the first structural insights regarding interactions of this family of inhibitors with plasmepsins. The compounds in this class are potent inhibitors of HIV-1 protease, but also show nM binding affinities towards plasmepsin IV. Here, we utilize automated docking, molecular dynamics and binding free energy calculations with the linear interaction energy LIE method to investigate the binding of allophenylnorstatine inhibitors to plasmepsin IV from two different species. The calculations yield excellent agreement with experimental binding data and provide new information regarding protonation states of active site residues as well as conformational properties of the inhibitor complexes.
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