Libraries optimisation

Figure 14.7 An illustration of library optimisation and selection using a multiobjective Pareto algorithm. The virtual library of 20000 compounds has a large number of compounds similar to existing molecules in the GSK collection, and the library is not structurally diverse, containing many close analogues. Selections of a 1920 combinatorial subset yield multiple solutions that have better complementarity to the GSK collection and are not made up of large numbers of close analogues. However, each library has certain advantages, as they are from the non-dominated set of solutions.

M, J P Bielawski, J C Hempel and M Waldman 1996. Optimisation and Visualisation of ecular Diversity of Combinatorial Libraries. Molecular Diversity 2 64-74. 

These catalysts were first tested as resin-bound derivatives via HTS, first with metals and then without. Three libraries of chiral molecules, based on three different enantiomerically pure diamines, bulky salicylidene moities and optically active ii-amino acids were used for structure optimisation (Scheme 37 TBSCN = fBuMe2SiCN) [152]. 

Hassan M, Bielawski JP, Hempel JC, Waldman M. Optimisation and visualisation of molecular diversity of combinatorial libraries. Mol Diversity 1996 2 64-74. 

Wright T, Gillet VJ, Green DVS, Pickett SD. Optimising the size and configuration of combinatorial libraries. J Chem Info Comput Sci 2003 43 381-90. 

LC-PB-MS is especially suited to NPLC systems. RPLC-PB-MS is limited to low-MW (<500 Da) additives. For higher masses, LC-API-MS (combined with tandem MS and the development of a specific mass library) is necessary. Coupling of LC via the particle-beam interface to QMS, QITMS and magnetic-sector instruments has been reported. In spite of the compatibility of PB-MS with conventional-size LC, microbore column (i.d. 1-2 mm) LC-PB-MS has also been developed. A well-optimised PB interface can provide a detection limit in the ng range for a full scan mode, and may be improved to pg for SIM analyses. 

Optimisation of software (generic format) would be auspicious, but even no generally accepted norms are available. Specialised MS, FTIR and ToF-SIMS computer-based industrial additive libraries are the necessary support for analytical developments. Web-based data mining tools are also starting to become available. 

Furness,L.M. Expression Databases for Pharmaceutical Lead Optimisation. Proceedings of the 13 Noordwijkerhout-Ca-merino Symposium [2001], Trends in Drug Research III. Pharmacochemistry Library, volume 32 Ed. H. van der Goot (Elsevier). 

Dihydroneopterin aldolase (Table 1, entry 8) Inhibitors (such as 33) of dihydro-neopterin aldolase were identified using high throughput X-ray-based fragment screening of a 10,000 member random library [43]. Structure-guided optimisation gave potent leads such as 35. 

In a first series of trials, trimethylsUyl cyanide (TMSCN) was used as the cyanide source and polymer-supported (ethylenediaminetetraacetic acid) ruthenium(lll) chloride as the Lewis acid catalyst (Scheme 23). After the optimisation of the conditions on a model reaction, a small library of compounds was produced, proving the concept by obtaining 100% yields in 2.5 h reaction time. Using flow rates of... 

Gillet, V. J., Willett, P, and Bradshaw, J. (1999) Selecting combinatorial libraries to optimise diversity and physical properties. J. Chem. Inf Comput. Sci. 39, 167-177. 

Mason, J. S. and Beno, B. R. (2000) Library design using BCUT chemistry-space descriptors and multiple four-point pharmacophore fingerprints simultaneous optimisation and structure-based diversity. J. Mol. Graph. Model. 18, 438-451. 

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