| Abstract: | ABSTRACT: 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 (HMG-CoA) reductase activity by small molecule inhibitors has been shown to inhibit hypercholesterolemia. METHODS: This article describes the development of a robust pharmacophore model and the investigation of structure activity relationship analysis of 43 N-iso-propyl pyrrole-based derivatives reported for HMG-CoA reductase inhibition. A five point pharmacophore model was developed and the generated pharmacophore model was used to derive a predictive atom-based 3D-QSAR model for the studied dataset. RESULTS: The obtained 3D-QSAR model has an excellent correlation coefficient value (r2 = 0.9566) 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 = 0.6719). 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. |
