Component libraries

McKenna, J. M., F. Halley, J. E. Souness, I. M. McLay, S. D. Pickett, A. J. Collis, K. Page, and I. Ahmed. An algorithm-directed two-component library synthesized via solid-phase methodology yielding potent and orally bioavailable p38 MAP kinase inhibitors, J. Med. Chem. 2002, 45, 2173-2184... 

The aim must be to invest in the development of a component library as a capital asset (see Figure 10.1). Like any investment, this one requires money to be spent for a while before any payback is seen. A conventional software development organization requires a considerable shift of attitudes and strategy to adopt a component-based approach. Like all... 

To us, a component architecture defines the schemes of how components can be plugged together and interact. This definition may vary from one project or component library to another and includes schemes such as CORBA, DCOM, JavaBeans, database interface protocols such as ODBC, and lower-level protocols such as TCP/IP as well as simpler sets of conventions and rules created for specific projects. 

Each project or component library can define its own connectors to suit itself. In the Motor example in Section 10.6.2, Kit of Small Components, we can identify two principal kinds of component connector ... 

In this pattern, you devote resources to build, maintain, and promote use of a component library. There is no free lunch. 

Another example of software for postacquisition data processing is the OpenLynx-Diversity system utilized on the Platform mass spectrometer (Micromass, UK) running within the Windows NT operating system. The software is specially designed for single-component libraries and requires information about the mass of the expected component in each well prior to data processing [56]. 

In the previous section we mentioned that requirements for reasonable separation of HPLC peaks in single-component libraries limit the throughput of HPLC/UV/MS analysis to about 100-200 samples per day per instrument. Thus, if the synthesis rate exceeds this level, either the number of instruments in the analytical laboratory has to be increased or methods of analysis should be altered. When the rate of synthesis becomes as high as 400-1000 individual compounds per day (which is not unusual today), most combinatorial chemistry companies change their analytical strategy. Basically, two approaches are used to cope with such a high synthesis rate limited analysis of all library components and detailed analysis of a certain percentage of the representative samples from a library. 

Recently several groups have begun to consider selecting molecules in product space. An N component library can be represented by an N dimensional matrix, for example, figure 2 illustrates a 2 dimensional matrix where the rows of the matrix represent the elements in one reactant pool, the columns represent the reactants in the second reactant pool and the elements of the matrix represent the product molecules formed by the combinatorial linking of the reactants in one pool with the reactants in the other. 

Pickett et al. [68] describe a program, DIVSEL, for selecting reactants while taking account of the pharmacophoric diversity that exists in the final products. They describe a 2-component library where the reactants in one pool are fixed and a subset of reactants is to be selected from the second pool. The virtual library is enumerated and a pharmacophore key is generated for each of the product molecules. Reactants are selected from the second pool using a dissimilarity-based compound selection process that represents a candidate reactant by a pharmacophore key that covers an ensemble of products. 

Figure 5.17. Screen-shots from ADEPT. (a)A simple two-component library composed of an ami-nothiazole template and a series of piperidines specified with ADEPT. (b) Histograms of rotatable bonds and molecular weight for the enumerated virtual library, aiding the medicinal chemist in the design of the library. [Reproduced from A. R. Leach and M. M. Hann, Drug Discovery Today, 5, 326-336 (2000), with permission of Elsevier Science.]...

Figure 13.6. (a) Partial negative ion electrospray mass spectrum of a 36-component library mixture. Both the measured mass and the difference between the measured and theoretical values (in ppm) are shown, (b) Negative ion electrospray spectrum of the 120-component library showing the resolution of three nominally isobaric peaks. (Reproducedfrom Ref. 24 ty permission of Bentham Science Publishers). 

Figure 8 (a) Negative ion ESI spectrum of the 36-component library sample showing the ppm differences between theoretical and found m/z values for the assigned peaks, (b) Negative ion ESI spectrum of the 120-component library sample resolving nominally isobaric peaks. (Reprinted from Ref. 91.)... 

CW Ross, MB Young, DR Patrick, HG Ramjit. the simultaneous characterization of multi-component libraries from single reaction wells by use of FT/ICR/ MS. Proceedings of the 45th ASMS Conference on Mass Spectrometry and Allied Topics, Palm Springs, CA, 1997, p. 1257. 

Improvement in LC-MS and LC-MS/MS analysis throughput has been reported by the use of monolithic silica columns to increase the speed of chromatography separation [156-158]. The substimtion of an SFC front end to MS in lieu of HPLC has been a growing trend in compound library analysis. It is possible that the use of SFC-MS will be extended to in vitro and in vivo evaluation of library compounds such as ADME and DMPK. CE-MS has not been widely used in the analysis of combinatorial libraries. To date, the application of CE-MS has been frequently in the analysis of mixture-component libraries derived from split synthesis and in the affinity screening of libraries through ACE. However, with the miniaturization of biological screening in the lab-on-a-chip format, CE-MS may find renewed interest... 

In the previous section we mentioned that requirements for reasonable separation of HPLC peaks in single-component libraries limit the throughput of HPLC/... 

Figure 2 Example separation of a 100-component library by HPLC [Hypersil BDS, Cg (3 [xm 200 X 4.6 mm) water-acetonitrile 3...

The amount of easily generatable chemical coiffigurations scales dramatically as users contribute components to mBuild s library. As such, we have begun curating a version-controlled library of components such that ffiey can be reused, error-corrected and added to. mBuild and its component library are fully open-sourced at https //github.com/imodels/mbuild and user contributions are actively encouraged, which we hope will attract an active user base. 

Component C is not available in the Component Library. Therefore, you need to create this component using Hypothetical. 

The certification object can be either a complete product or components in a product or in a component library. The certification can be used for internal development purposes, such as controlling the test process by relating the test stopping criteria to a specific reliability level, as well as externally as a basis for acceptance. 

Allocation - selecting the appropriate number of functional units, storage units and intercoimection units from available component libraries. 

---