| 1. |
- Barlind, Jonas G., et al.
(författare)
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Identification and design of a novel series of MGAT2 inhibitors
- 2013
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 23:9, s. 2721-2726
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Tidskriftsartikel (refereegranskat)abstract
- [Acyl CoA]monoacylglycerol acyltransferase 2 (MGAT2) is of interest as a target for therapeutic treatment of diabetes, obesity and other diseases which together constitute the metabolic syndrome. In this Letter we report our discovery and optimisation of a novel series of MGAT2 inhibitors. The development of the SAR of the series and a detailed discussion around some key parameters monitored and addressed during the lead generation phase will be given. The in vivo results from an oral lipid tolerance test (OLTT) using the MGAT2 inhibitor (S)-10, shows a significant reduction (68% inhibition relative to naive, p < 0.01) in plasma triacylglycerol (TAG) concentration.
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| 2. |
- Geschwindner, Stefan, et al.
(författare)
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Characterisation of de novo mutations in the C-terminal domain of proprotein convertase subtilisin/kexin type 9.
- 2015
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Ingår i: Protein Engineering Design & Selection. - : Oxford University Press (OUP). - 1741-0126 .- 1741-0134.
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Tidskriftsartikel (refereegranskat)abstract
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of the hepatic low-density lipoprotein receptor (LDL-R) and is therefore a prominent therapeutic target for reducing LDL-cholesterol. The C-terminal domain of PCSK9 is unlikely to be involved in a direct extracellular interaction with the LDL-R. We probed the importance of the C-terminus for the degradation of the LDL-R by designing seven de novo mutants of PCSK9 that fill potential druggable cavities. The mutants were tested for their ability to diminish LDL uptake in human HepG2 cells and for affinity towards a calcium independent mutant of the EGF(A) domain of the human LDL-R. The later was done by a newly developed surface plasmon resonance-based assay format. We identified three mutant proteins (G517R, V610R and V644R) with decreased ability to block LDL uptake into HepG2 cells. These mutations define areas outside the direct interaction area between PCSK9 and the LDL-R that could be targeted to inhibit the PCSK9 triggered degradation of the LDL-R. We also describe the mechanistic rationalisation of the affinity changes seen with the natural occurring human D374Y (gain of function) mutation causing severe hypercholesterolaemia. The action of this mutant is due to a significantly decreased dissociation rate constant, whereas the mutation does not affect the association rate constant.
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| 3. |
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| 4. |
- O'Mahony, Gavin, et al.
(författare)
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A practical synthesis of 2′-aminoacylamino-2′-deoxyadenosines
- 2007
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Ingår i: Tetrahedron. - : Elsevier BV. - 0040-4020. ; 63:29, s. 6901-6908
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Tidskriftsartikel (refereegranskat)abstract
- A practical and efficient synthesis of 2′-aminoacylamino-2′-deoxyadenosine derivatives is reported. EDCI/HOBt-mediated coupling of a 3′,5′-diprotected 2′-amino-2′-deoxyadenosine derivative to various N-Cbz-l-amino acid derivatives followed by global deprotection affords analytically pure 2′-aminoacylamino-2′-deoxyadenosine derivatives without the necessity for preparative HPLC purification. These compounds are non-hydrolysable isosteres of 2′-aminoacyladenosines, which are of use in X-ray studies for the elucidation of the editing mechanism of various tRNA synthetases.
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| 5. |
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| 6. |
- O'Mahony, Gavin, et al.
(författare)
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Synthesis of 2-([1,2,3]Triazol-1-yl)-2-deoxyadenosines
- 2008
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Ingår i: ChemInform. - : Wiley. - 0931-7597 .- 1522-2667. ; 27:5, s. 449-459
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Tidskriftsartikel (refereegranskat)abstract
- ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a Full Text option. The original article is trackable via the References option.
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| 7. |
- Park, Se Hyung, et al.
(författare)
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A luminescence-based protocol for assessing fructose metabolism via quantification of ketohexokinase enzymatic activity in mouse or human hepatocytes
- 2021
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Ingår i: STAR Protocols. - : Elsevier BV. - 2666-1667. ; 2:3
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Tidskriftsartikel (refereegranskat)abstract
- Ketohexokinase (KHK) catalyzes the first step of fructose metabolism. Inhibitors of KHK enzymatic activity are being evaluated in clinical trials for the treatment of non-alcoholic fatty liver disease (NAFLD) and diabetes. Here, we present a luminescence-based protocol to quantify KHK activity. The accuracy of this technique has been validated using knockdown and overexpression of KHK in vivo and in vitro. The specificity of the assay has been verified using 3-O-methyl-D-fructose, a non-metabolizable analog of fructose, heat inactivation of hexokinases, and depletion of potassium. For complete details on the use of this protocol, please refer to Damen et al. (2021).
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| 8. |
- Sukuru, Sai Chetan K, et al.
(författare)
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Discovering new classes of Brugia malayi asparaginyl-tRNA synthetase inhibitors and relating specificity to conformational change.
- 2006
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Ingår i: Journal of computer-aided molecular design. - : Springer Science and Business Media LLC. - 0920-654X .- 1573-4951. ; 20:3, s. 159-78
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Tidskriftsartikel (refereegranskat)abstract
- SLIDE software, which models the flexibility of protein and ligand side chains while docking, was used to screen several large databases to identify inhibitors of Brugia malayi asparaginyl-tRNA synthetase (AsnRS), a target for anti-parasitic drug design. Seven classes of compounds identified by SLIDE were confirmed as micromolar inhibitors of the enzyme. Analogs of one of these classes of inhibitors, the long side-chain variolins, cannot bind to the adenosyl pocket of the closed conformation of AsnRS due to steric clashes, though the short side-chain variolins identified by SLIDE apparently bind isosterically with adenosine. We hypothesized that an open conformation of the motif 2 loop also permits the long side-chain variolins to bind in the adenosine pocket and that their selectivity for Brugia relative to human AsnRS can be explained by differences in the sequence and conformation of this loop. Loop flexibility sampling using Rigidity Optimized Conformational Kinetics (ROCK) confirms this possibility, while scoring of the relative affinities of the different ligands by SLIDE correlates well with the compounds' ranks in inhibition assays. Combining ROCK and SLIDE provides a promising approach for exploiting conformational flexibility in structure-based screening and design of species selective inhibitors.
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