Pharmacophore identification by molecular modeling and chemometrics: The case of HMG-CoA reductase inhibitors

Summary A methodology based on molecular modeling and chemometrics is applied to identify the geometrical pharmacophore and the stereoelectronic requirements for the activity in a series of inhibitors of 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase, an enzyme involved in cholesterol biosynthesis. These inhibitors present two common structural features—a 3,5-dihydroxy heptanoic acid which mimics the active portion of the natural substrate HMG-CoA and a lipophilic region which carries both polar and bulky groups. A total of 432 minimum energy conformations of 11 homologous compounds showing different levels of biological activity are calculated by the molecular mechanics MM2 method. Five atoms are selected as representatives of the relevant fragments of these compounds and three interatomic distances, selected among 10 by means of a Principal Component Analysis (PCA), are used to describe the three-dimensional disposition of these atoms. A cluster analysis procedure, performed on the whole set of conformations described by these three distances, allows the selection of one cluster whose centroid represents a geometrical model for the HMG-CoA reductase pharmacophore and the conformations included are candidates as binding conformations. To obtain a refinement of the geometrical model and to have a better insight into the requirements for the activity of these inhibitors, the Molecular Electrostatic Potential (MEP) distributions are determined by the MNDO semiempirical method.