Pharmacophore generation and atom-based 3D-QSAR of N-iso-propyl pyrrole-based derivatives as HMG-CoA reductase inhibitors.

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Background: Coronary heart disease continues to be the leading cause of mortality and a significant cause of morbidity and account for nearly 30% of all deaths each year worldwide. High levels of cholesterol are an important risk factor for coronary heart disease. The blockage of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity by small molecule inhibitors has been shown to inhibit hypercholesterolemia. Herein, we describe the development of effective and robust pharmacophore model and the structure-activity relationship studies of 43N-iso-propyl pyrrole-based derivatives previously reported for HMG-CoA reductase inhibition.

Results: A 5-point pharmacophore model was developed and the generated pharmacophore model was used to derive a predictive atom-based 3D quantitative structure-activity relationship analysis (3D-QSAR) model for the studied dataset. The obtained 3D-QSAR model has an excellent correlation coefficient value (r2 = 0.96) along with good statistical significance as shown by high Fisher ratio (F = 143.2). The model also exhibited good predictive power confirmed by the high value of cross validated correlation coefficient (q2 = 0.672). Further, pharmacophoric model was employed for virtual screening to identify four potential HMG-CoA reductase inhibitors.

Conclusions: The QSAR model suggests that electron-withdrawing character is crucial for the HMG-CoA reductase inhibitory activity. In addition to the electron-withdrawing character, hydrogen bond--donating groups, hydrophobic and negative ionic groups positively contribute to the HMG-CoA reductase inhibition. These findings provide a set of guidelines for designing compounds with better HMG-CoA reductase inhibitory potential.