The rational design of conformationally flexible drugs is briefly reviewed and conformational flexibility is identified as a major stumbling block in the application of QSAR-type methods. With a worked example for thyroid stimulating hormone releasing factor (TRH) and analogues, an approach with several new features is described which leads to quantitative structure-function relationships for the analogues studied so far. With the advantage of hindsight, it appears that with proper treatment good structure-activity relationships might be expected even in the usual case of a receptor of unknown structure, and the reasons for this are described.
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