Jack johnson fragments meaning
(13−15) Covalent chemical probes and drugs have been developed against diverse proteins, including hydrolases, (16,17) kinases, (18−20) nuclear export proteins, (21) and oncogenic GTPases. (11,12)Ĭovalent ligands are attractive starting points for chemical probe and drug development for several reasons, including the potential to achieve improved potency for shallow binding pockets and increased residency time leading to more durable pharmacological action. (7−10) A subset of these approaches focuses on covalent ligand discovery, where electrophilic compounds are screened for reactivity against thousands of nucleophilic residues (e.g., cysteines, lysines) in the proteome. In recent years, chemical proteomic strategies have emerged that enable the discovery of ligands for proteins on a global scale directly in native biological systems. (1−3) While high-throughput screening methods that expose purified proteins to large compound libraries offer a well-established approach to chemical probe discovery, (4−6) many proteins are challenging to recombinantly express and purify and may further lack sufficient characterization for functional assay development.
Selective chemical probes are available for only a modest fraction of the human proteome. Our findings provide a road map to optimize covalent fragments into more advanced chemical probes without requiring protein purification or structural analysis.Ī strategy is described to convert electrophilic fragment-cysteine interactions discovered by chemical proteomics into high-throughput ELISA screens that do not require purified proteins. We use these assays to expediently optimize a weak potency fragment hit into a sub-μM inhibitor that selectively engages an active-site cysteine in the retinaldehyde reductase AKR1B10. Here, we show that broadly reactive electrophilic fragments, or “scouts”, can be converted into site-specific target engagement probes for screening small molecules against a wide array of proteins in convenient gel- and ELISA-based assay formats. Further optimization of these initial ligandability events without resorting to the time-consuming process of individualized protein purification and functional assay development, however, presents a persistent technical challenge. Chemical proteomic methods have been introduced that leverage electrophilic fragments to globally profile the covalent ligandability of nucleophilic residues, such as cysteine and lysine, in native biological systems.
In Pollock's The Underground Speaks, 1935 he records Mojo as "any kind of poisonous habit-forming narcotics (dope)".Covalent ligands are a versatile class of chemical probes and drugs that can target noncanonical sites on proteins and display differentiated pharmacodynamic properties. Mojo is also recorded as meaning cocaine/heroin etc. Then the world will know, the Hoochie-Coochie Man I'm gonna make you, pretty girl, lead me by the hand I got John the Conqueror, I'm gonna mess with you Muddy Waters had, like several others, used 'mojo' in earlier lyrics, for example, Hoochie-Coochie Man, 1954: I got my Mojo working but it just won't work on you I got my black cat bones all pure and dry I want to love you so till I don't know what to do Got my Mojo working but it just won't work on you Waters' version is a modification of the original lyric written by Preston Foster and first recorded by Ann Cole in 1956, which indicates that mojos were thought of as lucky charms for women as well as for men:
The 'mojo hand' would be a reference to a magic talisman - something like a lucky rabbit's foot. I'm gonna have all you women right here at my command I'm going down to Louisiana to get me a mojo hand I wanna love you so bad till I don't know what to do Got my mojo working, but it just won't work on you His well-known blues classic Got my mojo working, 1957, was the song that introduced the term to the wider world: Muddy Waters, would have heard work mojo as he was growing up in Mississippi. "The term mojo is often used by the Mississippi Negroes to mean 'charms, amulets, or tricks', as 'to work mojo' on a person or 'to carry a mojo'." In 1926, Newbell Niles Puckett published this definition in his Folk Beliefs of the Southern Negro:
The term was widely used in the US black communities at that time. More recently, this has been extended to mean power or influence of any kind. Meant voodoo or magical power, specifically one which gave the mojo's male possessor a sexual power over women. What's the origin of the phrase 'Got my mojo working'?