The Use of GADriven Evolutionary Experiments

As shown above, GAs are rather tolerant to experimental errors and may still yield good re suits even if the starting hypothesis is wrong. This behavior is especially true for false nega tive results, since these are simply eliminated in the selection step and are not remembered The elimination of misleading false positive results takes somewhat longer - depending or, how often a good chromosome is allowed to replicate. This "fuzzy" and robust optimization property makes GAs especially attractive for real time experimental optimizations as described above. Furthermore, for the application of GA-based evolutionary methods, similar to Nature, one does not need to know or to describe chemical structures explicitly, or to develop a structure-based hypothesis about SARs.

On the other hand, GAs also have serious drawbacks which could render them unattractive for real experiments. First, GAs are stochastic which means that they do not necessarily give the same results in each run. By its very nature, a GA "learns" in a sequential, implicit way over several cycles of selection and testing which could be prohibitive for time-consuming, or expensive synthesis, or biological testing. Therefore, the application of GA-driven compound selection seems appropriate especially if [21,22]:

• the search space is very large and multi-dimensional,

• the sequential synthesis and testing can be performed rapidly, and

• the structure-property relationship is multimodal.

Keeping these criteria in mind, we believe that there are many SPR problems that could be solved with success using GA-based compound selection. Such problems could involve more complicated selection criteria that include not only biological activities but also other properties like selectivity or penetration through biological membranes, which would increase the dimensionality of the SPR landscape. Other examples may include finding entirely new multi-component reactions that yield products exhibiting biological activities simply by varying various starting materials. The area of material sciences where new materials or new catalysts are composed by mixing predefined starting materials or components, and explicit descriptions of SPR are rare, seems amenable to evolutionary selection methods. A genetic algorithm has recently been used to propose new polymer molecules that mimic a given target polymer [23], or exhibit a range of glass transition temperatures and hydrophobic-ities [24], Although the number of polymers considered was not very large, this work represents a convincing example of diversity and similarity selection that was verified on the basis of experimental data in the field of materials discovery.

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Virtual Screening for Bloactlve Molecules

Edited by Hans-Joachim Böhm and Gisbert Schneider Copyright© VV1LEY-VCH Verlag GmbH, 2000

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