Optimizing combinatorial libraries

For any synthetic scheme, the key issue in combinatorial library design is monomer selection, the objective of which is to identify those monomers which when combined together provide the optimal combinatorial library. By optimal we mean that Uhrary which best meets the prescribed objectives it might be the most diverse, have the maximum number of molecules that could fit a 3D pharmacophore or a protein binding site, best match a particular distribution of some physicochemical property, or some combination of these or other criteria. An important consideration when designing a combinatorial Uhrary is the subset selection constraint. In a true combinatorial Ubrary of the form A x B x C, every molecule from the set of reagents A reacts with every molecule from B and every molecule from C to generate n xn x c product structures, where are the numbers of... 

Goldman, E. R. Youvan, D. C. (1992) An algorithmically optimized combinatorial library screened by digital imaging spectroscopy. Bio/Tcc/mo/ogy 10, 1557-1561. 

Fig. 6. Aqueous solubility for virtual compounds can be assessed using a suitable computational model, here one that estimates the logjo of the thermodynamic solubility of a compound in neat water at 25°C and 1 atm (41). The solubility profile of an optimized combinatorial library (solid line) is shifted to higher solubility by about two orders of magnitude, relative to the full virtual library (dashed line), as a result of optimization by MapMaker M in this example. Owing to the use of a fitness function (eq. 1), a more pronounced shift could be obtained at the expense of some chemical diversity in the resulting library.

P Willett, J Bradshaw and D V S Green 1999. Selecting Combinatorial Libraries to Optimize rsity and Physical Properties. Journal of Chemical Information and Computer Science 39 169-177. 1 and A W R Payne 1995. A Genetic Algorithm for the Automated Generation of Molecules in Constraints. Journal of Computer-Aided Molecular Design 9 181-202. 

Waldman M, Li H, Hassan M. Novel algorithms for the optimization of molecular diversity of combinatorial libraries. / Mo/ Graph Model 2000 18 412-26. 

Zheng W, Hung ST, Saunders JT, Seibel GL. PICCOLO a tool for combinatorial library design via multicriterion optimization. Pac Symp Biocomput 2000 588-99. 

Gillet VJ. Designing combinatorial libraries optimized on multiple objectives. Methods Mol Biol 2004 275 335-54. 

Agraflotis DK. Multiobjective optimization of combinatorial libraries. Mol Divers 2002 5 209-30. 

Closely related to the use of PSA in virtual screening is its application in the design of combinatorial libraries with optimal properties. These applications are reviewed further in Refs. [46, 47], for example. 

Two main factors have guided the need for optimization of the early screening techniques on one hand the use of simple, quick and high-capacity cell monolayer methods, e.g., Caco-2 cell and MDCK and on the other hand the increased synthesis of more lipophilic, insoluble compounds from combinatorial libraries. This has created a vast number of different variants of cell-based assays and has resulted in variability among the data obtained. A need for optimization of as many as possible of the different parameters in order to increase the predictivity and throughput of the model has been suggested in the literature [98-100]. 

First the primary combinatorial library of chiral ligands LI —L5 and chiral activators Al —A5 (Scheme 12) were studied in order to optimize the lead structure of the next generation of chiral ligands and activators.87,89... 

Combinatorial chemistry, 7 380-434 8 400—401 13 283-284. See also High-throughput experimentation applications, 7 381-383 commercial environment, 7 387-389 methodology, 7 383-387 microwaves in, 16 548-552 nomenclature, 7 380 polymers, 7 405—413 Combinatorial libraries, 12 515-517 Combinatorial methods, 7 380 Combinatorial optimization approach, in computer-aided molecular design, 26 1037... 

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