Target-guided synthesis

Figure 7.1 Schematic representation of target-guided synthesis to generate a ligand (guest) templated by a target biomolecule (host) using the lock and key descriptors of Emil Fischer.

Target-Guided Synthesis or Freeze-Frame Click Chemistry... 

A. E. Lund One part of me likes very much the idea of using in vitro assays to hint at selectivity between insects and mammals. However the problem that frequently arises if one tries to use such assays to guide synthesis is a marked discomfort in making synthesis decisions based on these results. If one limits synthesis to an area of chemistry with target site selectivity, one is haunted by the concern that the most selective compound in vivo is one that is less selective on the target site because it possesses some toxicokinetic vulnerability in mammals. On the other hand, compounds which are inactive on the mammalian target may ultimately be less safe because of a deleterious action on some totally unrelated system in the mammal. So the discrepancies between selectivity measured in vivo and in vitro cloud our ability to make synthesis decisions with much confidence. Perhaps if one continually compares in vivo and in vitro results with a group of compounds, you can minimize these errors. 

The first synthesis of a P-amyrin derivative was accomplished by a convergent route which depended on cation-olefin cyclization to form the critical central ring. The plan of synthesis was largely guided by the selection of SM goals for the A/B and E ring portions of the target. 

Part Three is intended to balance the coverage of Parts One and Two and to serve as a convenient guide to the now enormous literature of multistep synthesis. Information on more than five hundred interesting multistep syntheses of biologically derived molecules is included. It is hoped that the structural range and variety of target molecules presented in Part Three will appeal to many chemists. 

For targets that lack structural information, such as GPCRs or ion channels, a pharmacophore model or multiple pharmacophore models for different series of compounds can explain SAR and guide the synthesis of new analogs. Alternatively, homology models based on bacteriorhodopsin have been used to explain the interactions of small molecules with GPCRs. 

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