| 1. |
- Friedman, Ran, et al.
(författare)
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Discovery of plasmepsin inhibitors by fragment-based docking and consensus scoring
- 2009
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Ingår i: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 4:8, s. 1317-1326
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Tidskriftsartikel (refereegranskat)abstract
- Plasmepsins (PMs) are essential proteases of the plasmodia parasites and are therefore promising targets for developing drugs against malaria. We have discovered six inhibitors of PM II by high-throughput fragment-based docking of a diversity set of ∼40 000 molecules, and consensus scoring with force field energy functions. Using the common scaffold of the three most active inhibitors (IC50=2–5 μM), another seven inhibitors were identified by substructure search. Furthermore, these 13 inhibitors belong to at least three different classes of compounds. The in silico approach was very effective since a total of 13 active compounds were discovered by testing only 59 molecules in an enzymatic assay. This hit rate is about one to two orders of magnitude higher than those reported for medium- and high-throughput screening techniques in vitro. Interestingly, one of the inhibitors identified by docking was halofantrine, an antimalarial drug of unknown mechanism. Explicit water molecular dynamics simulations were used to discriminate between two putative binding modes of halofantrine in PM II.
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| 2. |
- Gabel, Detlef, et al.
(författare)
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The Anionic Boron Cluster (B(12)H(11)SH)(2-) as a Means To Trigger Release of Liposome Contents.
- 2007
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Ingår i: ChemMedChed. - : Wiley. - 1860-7179. ; 2:1, s. 51-53
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Tidskriftsartikel (refereegranskat)abstract
- Triggered release. Liposomes are novel carriers for pharmaceutical agents and can be triggered to release their contents by the addition of B12H11SH, a compound in clinical use. As systemic toxicity is decreased relative to the free drug, liposomal drugs can therefore be administered in higher concentrations before dose-limiting side effects are met. Thus, liposome-encapsulated drugs may be of great value in the therapy of diseases.
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| 3. |
- Norinder, Ulf, et al.
(författare)
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Prediction of ADMET Properties
- 2006
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Ingår i: ChemMedChem. - : Wiley-VCH. - 1860-7179 .- 1860-7187. ; 1:9, s. 920-937
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Forskningsöversikt (refereegranskat)abstract
- This Review describes some of the approaches and techniques used today to derive in silico models for the prediction of ADMET properties. The article also discusses some of the fundamental requirements for deriving statistically sound and predictive ADMET relationships as well as some of the pitfalls and problems encountered during these investigations. It is the intension of the authors to make the reader aware of some of the challenges involved in deriving useful in silico ADMET models for drug development.
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| 4. |
- Odell, Luke R, et al.
(författare)
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Azido and diazarinyl analogues of bis-tyrphostin as asymmetrical inhibitors of dynamin GTPase
- 2009
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Ingår i: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 4:7, s. 1182-1188
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Tidskriftsartikel (refereegranskat)abstract
- Probing the dynamin binding site: Bis-tyrphostin (1, Bis-T), is a potent inhibitor of the phospholipid-stimulated GTPase activity of dynamin I. Analogues of Bis-T have significant potential as a biological probes for the dissection of endocytic pathways. Bis-T-derived compounds were synthesised and evaluated for their ability to inhibit the GTPase activity of dynamin I. Two analogues (23 and 24) represent the first asymmetrically substituted Bis-T analogues to retain dynamin inhibition.Two azidobenzyl amide (4 and 23) and one 3-trifluoromethyl-3H-diazirin-3-ylphenyl (24) analogues of bis-tyrphostin (1, Bis-T) were synthesised as potential photoaffinity labels for the elucidation of the binding site of compound 1 in dynamin I. Of the two azidobenzyl amide analogues (4 and 23), the terminally substituted 23 retained dynamin I GTPase inhibition (IC(50)=6.4+/-2.8 microM) whilst 4, which was substituted on the central carbon of the amide linker, displayed no activity. Analogue 24 also retained inhibitory activity (IC(50)=36+/-9 microM). Photoaffinity labelling experiments did not unequivocally elucidate the binding pocket of compound 1. However, compounds 23 and 24 represent the first asymmetrically substituted Bis-T analogues to retain dynamin inhibitory activity, providing a new direction for analogue synthesis.
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| 5. |
- Norinder, U, et al.
(författare)
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Prediction of ADMET Properties.
- 2006
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Ingår i: ChemMedChem. - 1860-7179. ; 1:9, s. 920-937
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Tidskriftsartikel (refereegranskat)
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