Abstract
BackgroundCoronary 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.ResultsA 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.ConclusionsThe 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.
Highlights
We have developed a quantitative pharmacophore model based on hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors collected from the same laboratory [18]
Dataset A set of 43N-iso-propyl pyrrole-based derivatives with well-defined HMG-CoA reductase inhibitory activity was used for the QSAR analysis [18]
We have used conformation suggested by the hypothesis for generating 3D quantitative structure–activity relationship analysis (3D-QSAR) model to identify overall aspects of molecular structure that govern the activity
Summary
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. The blockage of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity by small molecule inhibitors has been shown to inhibit hypercholesterolemia. High levels of cholesterol are linked to atherosclerosis, which is the accumulation of cholesterol-rich fatty deposits in arteries. This can cause arteries to narrow or become blocked, slowing or stopping the flow of blood to vital organs, especially the heart, brain and kidney [1,2,3,4,5]. Atherosclerotic heart disease is the leading cause of death, accounting for one-third of all deaths and atherosclerotic interference with blood supply to the brain (ischemic stroke) is the third most common cause of death after cancer [6,7,8,9]. A novel series of HMG-CoA reductase inhibitors, which can selectively inhibit HMG-CoA reductase with high inhibitory activities, has been reported by Pfefferkorn et al [18]
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