Drug lead compound identification increasingly uses high‐throughput screening in conjunction with computational methods. Hits found in this way are generally of low affinity (typically about 10−5 M) and require further development. Such low affinity can result in significant changes in binding mode upon change of experimental conditions: at pH 7, the Factor Xa inhibitor 1 (see picture) binds in the specificity pocket of trypsin through its pyridinyl group (yellow); at pH 8, the same pocket is occupied by the chloronaphthyl moiety (magenta), with a significant reorganization of the ligand binding site (circled).

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SummavyPorphobilinogen (1) , [aH]-la%eXed in the propionic residue, is synthesised by a short route and is used to establish that both vinyl groups of protoporphyrin-IX are biosynthesised by overall antiperiplanar elimination of a proton and carbon dioxide. 731 and refs. therein.

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