MTD–CoMSIA modelling of HMG-CoA reductase inhibitors

Abstract

The 3D quantitative structure–activity relationship for a series of hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors based on the pyrrolylethyl-tetrahydropyranone scaffold was examined using the Minimal Topological Difference (MTD) method and comparative molecular similarity index analysis (CoMSIA). The studied compounds were of the tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran-2-one type. In clinical practice, HMG-CoA reductase inhibitors are usually referred to by the generic name statins. The analysis performed using the MTD method showed that voluminous substituents produce a significant biological activity (= 0.677 > 0.5; SEECV = 0.319), while the CoMSIA method added useful information regarding the influence of the steric, electrostatic, hydrophobic, hydrogen bond donor, and acceptor properties on biological activity (= 0.60; r2 = 0.98).

Keywords

• statins
• molecular modelling
• correlations
• 3D-quantitative structure–biological activity