Sequential Simplex Optimization SSO

P s The average of the retained points in the case of a triangular simplex, this is the biseaion point on the line between the two highest vertices 

The initial large simplex guarantees that the topography will include the true maximum and that the available factor space will be represented in the initial set. This makes a large simplex particularly valuable in the investigation of lead molecules that are generated by random screens. Such compounds can be quickly evaluated for overall potential using SSO. If the initial set does not show promise, the optimization can be abandoned without concern that the true maximum was missed. 

After an initial six compound set, five refleaions were required to reach a maximum in activity for the general structure shown below. The most active compound in the series was over 1,000 times as potent as the lead. 

The application of the approach in three- or higher dimensional space requires a computer program. This can be written simply. The code for a Pascal version of the algorithm has been published.  

The successful application of the QSAR paradigm requires that effective experimental design strategies be applied from the very beginning of an optimization project. These strategies involve the selection of substituents to ef- 

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Since we wished to optimize this series with a minimal expenditure of our synthetic resources, the sequential simplex technique (SSO) was selected (11,12). This strategy is very resource efficient, requiring only n + 1 compounds to start the optimization, where n is the number of physiochemical parameters used to describe the characteristics of a substituent. We selected pi to account for lipophilicity and field (F) and resonance (R) were used to describe the electronic effects of each substituent (14). Verloop s Sterimol parameters (H), minimum van der Waals radius (B] ) and length (L) were selected to describe the size of the substituent. Using cluster analysis, we selected a set of six substituents that cover physiochemical parameter space well (15). These are-listed in Figure 6. 

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