COMPOUND LIBRARIES AND THEIR USES

Introduction: Concept

Drug design and discovery does not happen by chance but is a process of active searching by individual scientists. Often a template molecule (of proven biological activity) will be taken and systematically altered in small ways to generate whole series of structurally related compounds. These compounds can then be either tested against the original target disease or screened against a panel of diseases to find those molecules which processes biological activity. This process is extremely labor intensive and any means by which the cost of the search or the testing for activity can reduced is actively sort. A compound library is such a labor reducing facility [1]. A simple library will consist of information regarding properties of a number of compounds; this could include such things as structure, physical properties, chemical properties, purities or even synthesis patterns. A more complex library could be would consists if small amounts of actual compounds in known concentrations accompanied by all the known physical and chemical properties. This type library can be for the high through put screening for compounds of interest, whether they be of biological importance or synthetic chemical importance [2]. The key point of any library is the number and purity of the compounds contained within it. These could run into thousands of individual molecules. Obviously this approach means that a chemical library is a valuable item and many types of chemical libraries can be found commercially. Typical examples of the available library are “epigenetics libraries”, “known biological active molecules library” or even a “natural product extracts library”. The concept of a compound library is flexible in its design and structure; it can be adapted to virtually any series of chemicals, molecules or proteins that a researcher requires in course of his/her work, be that medical or industrial.

Compound libraries: Creation

One of the oldest compound libraries known is the “Treatise of medical diagnosis and prognoses” discovered in a series of ancient tablets dating back to the Mesopotamian period. These tablets not only contain medical information on treatment but the synthesis routes to formulate the medicine. More up-to-date than this is the Beilstein database which contains listings for over 9.5 million compounds gleaned from literature since 1771 [3]. However, these sort of libraries are great for reference but do not assist the researcher in his/her quest to find either the perfect catalyst or the one molecule that cures a disease. Smaller more specific libraries have generated which contain in addition to the standard structural, physical and chemical information but a dissolved sample of the actual compound itself [4-9]. Creation of such libraries relies on the current focus of research, since these focused libraries tend to be commercial products, the number of compounds in such libraries tend to be below 200 making their use manageable and relevant [2;10-12]. The non commercial compound libraries are the ones a researcher generates for him/herself of a series of molecules based on the “skeleton or backbone” of a molecule with known function, either biological or chemical [13-16]. These libraries tend to be smaller, in the 20-30 compounds range, and focused on one type of molecule. A library, on the other hand, which screens for an enzymatic activity, would contain structurally different molecule but each with a proven activity against a known enzyme. The larger the number of compounds used in the screening the greater the likelihood of a “hit” being found. Once a hit has been discovered then this molecules and those similar to item are carried through into the next phase of drug discovery

 

Compound Libraries: Commercial sources and types available

Commercially chemical databases are widely available in the open market ranging in price from $1200 of an 80 compound screen to $15000 for a chemical series 320 compounds. Larger or more diverse series of libraries tend to be owned by intuitions that will; for a fixed fee; run a screening of your enzymes or compounds for you.

References

    1.    Matter H. Computational approaches towards the quantification of molecular diversity and design of compound libraries. EXS 2003;(93):125-156.

    2.    Akella LB, DeCaprio D. Cheminformatics approaches to analyze diversity in compound screening libraries. Curr Opin Chem Biol 2010; 14(3):325-330.

    3.    Schneider G. Trends in virtual combinatorial library design. Curr Med Chem 2002; 9(23):2095-2101.

    4.    Blomberg N, Cosgrove DA et al. Design of compound libraries for fragment screening. J Comput Aided Mol Des 2009.

    5.    Jacoby E. Designing compound libraries targeting GPCRs. Ernst Schering Found Symp Proc 2006;(2):93-103.

    6.    Moir DT, Di M et al. Development and application of a cellular, gain-of-signal, bioluminescent reporter screen for inhibitors of type II secretion in Pseudomonas aeruginosa and Burkholderia pseudomallei. J Biomol Screen 2011; 16(7):694-705.

    7.    Paran Y, Lavelin I et al. Development and application of automatic high-resolution light microscopy for cell-based screens. Methods Enzymol 2006; 414:228-247.

    8.    Thompson S, Messick T et al. Development of a high-throughput screen for inhibitors of Epstein-Barr virus EBNA1. J Biomol Screen 2010; 15(9):1107-1115.

    9.    Gund P. Empirical vs. "rational" methods of discovering new drugs. Pac Symp Biocomput 1999;438-443.

  10.    Langer T, Krovat EM. Chemical feature-based pharmacophores and virtual library screening for discovery of new leads. Curr Opin Drug Discov Devel 2003; 6(3):370-376.

  11.    Klekota J, Roth FP. Chemical substructures that enrich for biological activity. Bioinformatics 2008; 24(21):2518-2525.

  12.    Stahura FL, Xue L et al. Methods for compound selection focused on hits and application in drug discovery. J Mol Graph Model 2002; 20(6):439-446.

  13.    Ferreira CV, Justo GZ et al. Natural compounds as a source of protein tyrosine phosphatase inhibitors: application to the rational design of small-molecule derivatives. Biochimie 2006; 88(12):1859-1873.

  14.    Murray JK, Sadowsky JD et al. Exploration of structure--activity relationships among foldamer ligands for a specific protein binding site via parallel and split-and-mix library synthesis. J Comb Chem 2008; 10(2):204-215.

  15.    Nilsson M, Hamalainen M et al. Compounds binding to the S2-S3 pockets of thrombin. J Med Chem 2009; 52(9):2708-2715.

  16.    Yoo B, Kirshenbaum K. Peptoid architectures: elaboration, actuation, and application. Curr Opin Chem Biol 2008; 12(6):714-721.