Diverse monomer selection

Lewell, X.Q. and Smith, R. Dmg-motif-based diverse monomer selection method and application in combinatorial chemistry. J. Mol. Model. 1997, 15, 43-48. 

Monomer selection may be significantly assisted by a different perspective, that is the computational evaluation of the reaetivity of each potential monomer belonging to a virtual set. In fact, it may well happen that a suitable, diversity-adding selected monomer has a poor reaetivity in the hbrary reaction scheme that will eventually... 

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... 

Bisphenols is a broad term that includes many chemicals with the common chemical structure of two phenolic rings joined together by a bridging carbon. Bisphenol A is a monomer widely used in the manufacture of epoxy and phenolic resins, polycarbonates, polyacrylates and corrosion-resistant unsaturated polyester-styrene resins. It can be found in a diverse range of products, including the interior coatings of food cans and filters, water containers, dental composites and sealants. [4]. BPA and BP-5 were selected for testing by the whole... 

Just in the USA during 2001, the man-made plastic fiber industry had over 90 plants with sales of 13 billion and employed about 45,000 people. Fabrication processes are diverse both in technology and equipment design. They have common steps that include preparation of reactants, polymerization, plastic recovery, plastic extrusion, and supporting operations. In some preparation operations, solvents are used to dissolve or dilute monomer and reactants. Solvents are also used to facilitate the transportation of the reaction mixture throughout the plant, to improve heat dissipation during the reaction, and to promote uniform mixing. Solvent selection is optimized to increase monomer... 

When the library individuals are filtered with physicochemical parameters, the nature of the scaffold becomes fundamental. As an example, if a maximum accepted value of log P (partition coefficient between n-octanol and water) of 4 is set as a limit, the use of a functionalized scaffold with log P = 6 will enormously limit the selection of monomers to highly hydrophilic structures, while the selection of a more appropriate scaffold would allow a higher degree of diversity while respecting the imposed filter. The same is true for monomers. For example, if an upper hmit of 600 is imposed for the molecular weight (MW) of the final library components, the use of monomers with an MW higher than 250-300 will not be acceptable. 

If we consider the example of Fig. 5.10, when the reagents are selected to produce a20x lOx 10 = 2000-membered library we end up with combined monomer sets composed of 40, rather than 3500, individuals (Fig. 5.11, top). If the 2000 most diverse library components are selected from the product space (Fig. 5.11, bottom), it may be that a significant fraction, or even all, the virtual monomers from one set must be used to prepare them, so that the library cost, in terms of both reagents and human effort, is not significantly reduced. This selection problem was noticed (31) during the selection from a virtual library of the 1600 most diverse amides, which were found to contain 137 amine and 146 carboxylic acid building blocks (19,992 possible combi-... 

Various kinds of polymerization, polyaddition, substitution and polycondensation reactions of monomers bearing stabilizing moieties have been involved. Almost every kind of synthetical approach has been tested. However, only some of them are of practical interest Examples of monomers and/or of the respective ma-cromolecular systems proposed as stabilizers were selected from many literature data to show the diversity of structures. Only representative references are reported. 

This procedure marks the end of the spatial component of the library synthesis. The resin beads in the wells identified to proceed in the library synthesis are mixed and then split out into a 96-well reaction block. All 96 reaction wells are indistinguishable and consist of compounds that have all possible A-B combinations. Monomer set C typically consists of 96 unique monomers, where one unique monomer C is coupled in each well for the third point of diversity. QC is conducted after completion of the final synthesis step by the selection of a minimum of 12 beads from each well. The sampling rate does not permit the calculation of relative synthetic yields for all compounds in the library however, a global assessment on synthesis for each monomer C is produced. A narrow bandwidth of mass spectral-relative yields of the final product is selected for assay and assures a tight-Ugand concentration band. Those monomers that fail after the last synthetic step are not forwarded to biological assays. This synthetic scheme can produce a 36,864 compound library that is characterized by approximately 4200 mass-spectral data points. Normally, the final library size is between 20 and 30K after removal of the identified synthetic failures during the QC process. 

---