3-HYDROXY-3-METHYLGLUTARYL-COENZYME-A REDUCTASE - 3-DIMENSIONAL STRUCTURE-ACTIVITY-RELATIONSHIPS AND INHIBITOR DESIGN

The inhibition of HMG-CoA reductase is an efficient way to lower plasma chlosterol levels in humans. The 9,9-bis (4-fluorophenyl)-3,5-dihydroxy-8-(substituted)-6,8-nonadienoic acids analogues represent a novel class of HMG-CoA reductase inhibitors developed at Bristol-Myers. The goal of this study was to delineate from inhibitory potency values the main topographical and physico-chemical features of the binding site probed by the substituent attached to the C-8 position of the analogues. Using a combination of receptor mapping and 3D-QSAR it was possible to obtain a quantitative map of the binding site which relates the HMG-CoA reductase inhibitory potency to the shape and size of both the binding site and C-8-substituent of the inhibitor. We prove that the 3D-QSAR derived here is reliable, robust, and affords predictive utility.