Designed inhibitors (like 1) of IspF, a key enzyme in the non‐mevalonate pathway for terpene biosynthesis and a potential antimalarial target, were synthesized and evaluated. Since fluorescent probes were introduced in these ligands, their affinity towards IspF from E. coli could be determined by fluorescence titrations. The binding modes of two ligands in ternary complexes with IspF and a ZnII ion were clarified by X‐ray analysis.
Purpose
The purpose of this paper is to understand whether a woodland-based intervention might offer something helpful and engaging for people affected by dementia. In total, 18 people came to Woodland Wellbeing groups over summer and autumn in 2016.
Design/methodology/approach
The authors made observations during the groups, kept some notes and conducted some interviews around three months after people had participated in Woodland Wellbeing.
Findings
Feedback from participants indicated themes around connection with nature and to one another; the joy in new learning and activities; and the inspirational impact of feeling part of nature.
Originality/value
This paper adds to the growing literature on natural approaches in supporting the wellbeing of people affected by dementia, and highlights the value of partnership working.
The nonmevalonate route to isoprenoid biosynthesis is essential in Gram-negative bacteria and apicomplexan parasites. The enzymes of this pathway are absent from mammals, contributing to their appeal as chemotherapeutic targets. One enzyme, 2C-methyl-d-erythritol-2,4-cyclodiphosphate synthase (IspF), has been validated as a target by genetic approaches in bacteria. Virtual screening against Escherichia coli IspF (EcIspF) was performed by combining a hierarchical filtering methodology with molecular docking. Docked compounds were inspected and 10 selected for experimental validation. A surface plasmon resonance assay was developed and two weak ligands identified. Crystal structures of EcIspF complexes were determined to support rational ligand development. Cytosine analogues and Zn2+-binding moieties were characterized. One of the putative Zn2+-binding compounds gave the lowest measured KD to date (1.92 ± 0.18 μM). These data provide a framework for the development of IspF inhibitors to generate lead compounds of therapeutic potential against microbial pathogens.
Strukturbasiert entworfene Hemmstoffe (wie 1) von IspF, einem Schlüsselenzym im „Nicht‐Mevalonat‐Weg“ der Terpenbiosynthese, wurden synthetisiert und auf ihre biologische Aktivität untersucht. Ihre Affinität gegen IspF aus E. coli wurde durch Fluoreszenztitration bestimmt. Der röntgenographisch ermittelte Bindungsmodus von zwei Liganden in Komplexen mit IspF und einem ZnII‐Ion liefert Erkenntnisse für die Entwicklung niedermolekularer, Wirkstoff‐ähnlicher Hemmstoffe.
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