Virtual molecular library

Molecular structure generation. Combinatorial chemistry requires the generation of virtual molecular libraries, usually defined by given reactants and reactions. For this reason we shall describe algorithms for reaction-based structure generation. 

Existence/nonexistence of a compound is certainly an important topic of chemistry, but depends on the state-of-the-art of chemical synthesis and survey of natural occurrence. In Chapters 7 and 8 we shall consider other properties of compounds, including less variable properties. We shall try to deduce experimental properties horn the chemical structure and vice versa. For this purpose it is crucial to generate in silica molecular structures with prescribed structural properties in silica, i.e. to generate virtual molecular libraries. The most important tools for this task will be described in Chapter 5. 

In general, the described techniques provide an effective, flexible, and relatively fast solution for library design based on analysis of bioscreening data. The quantitative relationships, based on the assessment of contribution values of various molecular descriptors, not only permit the estimation of potential biological activity of candidate compounds before synthesis but also provide information concerning the modification of the structural features necessary for this activity. Usually these techniques are applied in the form of computational filters for constraining the size of virtual combinatorial libraries and... 

The ability of MoSELEGT to simultaneously optimize molecular weight and diversity was tested in the selection of 30 x 30 combinatorial subsets of a 10000-member virtual amide library. It was shown that as the selection progressed, there was an improvement in both the molecular weight and diversity, as well as a spread of nondominated solutions across the Pareto frontier. The 17 nondominated solutions found after 5000 iterations emphasized the competing nature of these two objectives - those with lower... 

M.S. Virtual compound libraries a new approach to decision making in molecular discovery research. /. Chem. Inf Comput. Sci. 1998, 38, 1010-1023. 

Hue, I. Lehn, J. M. Virtual combinatorial libraries Dynamic generation of molecular and supramolecular diversity by self-assembly. Proc. Natl. Acad. Sci. U.S.A. 1997,94,2106-2110. 

Finally, the 3D-LogP descriptor may be used for the 3D screening of virtual molecular conformation libraries wherein the selection of candidate molecules might not only be driven by pharmacophoric but also by physicochemical constraints. Similarly, we anticipate that the 3D-LogP descriptor will also become useful for the design of chemical libraries in which the description of the conformational space is taken into account in the description of the constituent molecules. We are currently enhancing the descriptor by implementing the last atom type classification system proposed by Wildman and Crippen (54). 

Generation of a virtual combinatorial library by finding substituents of a custom scaffold that can be accommodated in the binding site of a molecular target or meet other 3D structural criteria. Once the virtual library is synthesized in the computer, individual members can be selected using structural or additional criteria and synthesized using automated equipment. 

S. Makino, T. J. A. Ewing, and I. D. Kuntz. DREAM++ Flexible docking program for virtual combinatorial libraries. Journal of Computer-Aided Molecular Design, 13 513-532, 1999. 

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