The predicted binding to the PGA1 site also aligned well with our SAR observations: Increased potency of the acrylic acid analog 36 could be rationalized by its higher rigidity and preorientation of the carboxylic acid to engage contacts with Arg515 and His516 (Figure ). Moreover, the relative solvent exposure of the aliphatic chain of the scaffold supported the lack of an eutomer for the chiral analogs 35 and 46 which formed similar poses for both absolute configurations (Figure , d and Figure ) with the bulky substituents oriented towards the solvent.