3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase: Molecular Modeling, Three-Dimensional Structure-Activity Relationships, Inhibitor Design

The 9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(substituted)-6, 8-nonadienoic acid analogues represent a novel class of HMG-CoA reductase inhibitors developed in our laboratories. We delineate from inhibitory potency values the main topographical and physicochemical features of the binding site probed by substituents attached to the C8 position of the analogues. Using a combination of receptor mapping and 3D-QSAR techniques, it was possible to determine a logical candidate for the conformation of the inhibitor bound to the receptor and to derive a reliable 3D-QSAR which relates the HMG-CoA reductase inhibitory potency to the shape and size of both the binding site and C8-substituent of the inhibitor. We show that the 3D-QSAR derived here affords predictive utility.