Small molecule modulators of protein

In chemogenomics and drug discovery, the most challenging task is to find small molecule modulators of protein function that specifically modulate the protein function of interest. Combinatorial chemistry has emerged as a powerful tool to address this problem by generation of large compound... 

Compound libraries as sources for small molecule modulators of protein function... 

The Challenge to Make Small-Molecule Modulators of Protein Function... 

F. Civoli, J. Watson, An ultra-HTS process for the identification of small molecule modulators of orphan G-protein-coupled receptors, Drug Discov. Today 2003, 8, 785- 792. 

The reverse chemical genetic approach begins the discovery of a small molecule modulator of a specific target protein. The small molecule is usually identified... 

Screens for small-molecule modulators of biological pathways typically utilize cultured cell lines, purified proteins, or, recently, model organisms (e.g., zebrafish. Drosophila C. elegans). Herein, we describe a method for using Xenopus laevis egg extract, a biologically active and highly tractable cell-free system that recapitulates a legion of complex chemical reactions foimd in intact cells. Specifically, we focus on the use of a luciferase-based fusion system to identify small-molecule modulators that affect protein turnover. 

While S. pombe strains carrying mutations that lower PKA activity can be detected by their ability to form colonies on solid medium lacking uracil [2], this phenotype is not sufficiently robust for HTSs to detect compounds that reduce PKA activity. Recently, we constructed zn. fbpl-driven GFP reporter that allows for small-molecule screens to detect compounds that stimulate PDF activity or inhibit AC (or their associated Gas) or PKA proteins [9]. Cell-based assays utilizing the fbpl-um4 and/ pi-GFP reporters allow for inexpensive HTSs for small-molecule modulators of cloned PKA pathway genes expressed in S. pombe. 

Berg, T. (2003). Modulation of protein—protein interactions with small organic molecules. Angew Chem. Int. Ed. Engl. 42, 2462—2481. 

The ligand binding or catalytic sites are the most relevant parts of a protein domain for the development of small molecules as modulators of protein function. There is evidence that proteins with conserved folds often also have their functional sites on the same topological location. In some cases a remarkable conservatism in functional sites can be observed. This is true for the example described later in this review on similarity of Cdc25A phosphatase, acetylcholinesterase (AChE) and 1 Ifl-hydroxysteroid dehydrogenases (1 l HSD) (Fig. 9). Nevertheless, it should be stressed that the correlation patterns of amino acid sequence, protein fold and protein function remain a matter of debate. Moreover, a vast number of specific functions can be carried out by the limited number of protein domains due to the high amino acid diversity of proteins with similar folds. " ... 

D.M. Watterson, S. Mirzoeva, L. Guo, A. Whyte, J.J. Bourguignon, M. Hibert, J. Haiech and L.J. Van Eldik, Ligand modulation of glial activation cell permeable, small molecule inhibitors of serine-threonine protein kinases can block induction of interleukin 1 beta and nitric oxide synthase II, Neurochem. Int. 39 (2001) 459-468. 

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