The Well-Designed Substituent Set

With a lead in hand, the first problem is the selection of the initial set of substituents to make. Ideally, this step involves selection of a set of substituents that represents the whole universe of factors involved in the activity of the lead compound and does so with the smallest number of compounds possible. If this step is not done well, there is a high probability that the resultant QSAR analysis will not be successful. For example, Martin and Panas present evidence that poor series design can be the cause of a failure to find a QSAR model for activity. Conversely, adoption of strategies for the proper selection of substituent sets may be all that is needed to dramatically increase the efficiency of the design process and ensure the development of QSAR models. Indeed Martinhas suggested It is the opinion of many in the QSAR field that if the only contribution of QSAR to medicinal chemistry were to emphasize the importance of objective Series design, this in itself would be a major contribution to increased efficiency.  

The criteria used for selection of that initial set are to a great extent dependent on the overall strategy being followed. Indeed, we can divide the strategies based on the method used to select substituents as indicated in Table 1. 

Several authors have suggested criteria for an ideal substituent set (see Martin and Panas, Wootten, et al., and Wooldridge ). The major requirements expressed by these authors are collected in the following list  

The set should cover all factors that affect aaivity. 

The substituents chosen should cover the selected factor space as completely as possible. 

---